PERJETA

Page 1 of 2

Perjeta

Vials 420mg/14ml

יאמ

2019

/14ml

420mg

®

Perjeta

הט'גרפ

420

/ ג"מ

14

ל"מ

Pertuzumab

Concentrate for solution for infusion

,ה/רקי ת/חקור ,ה/רקי ה/אפור

מ"עב )לארשי( הקיטבצמרפ שור תרבח תשקבמ

םינוכדע רפסמ לע םכעידוהל

לש אפורל ןולעב רישכתה הט'גרפ םינוכדע קר םיניוצמ וז העדוהב .

.הרמחה םיווהמ רשא םינוכדעו םייתוהמ

יוותהה תו

ה

מושר תו

ל

רישכת :לארשיב

Metastatic Breast Cancer:

Perjeta is indicated in combination with trastuzumab and docetaxel for the treatment

of patients with HER2 positive metastatic breast cancer who have not received prior

anti-HER2 therapy or chemotherapy for metastatic disease.

Early breast cancer:

Perjeta is indicated for use in combination with trastuzumab and docetaxel for the

neoadjuvant treatment of patients with HER2-positive, locally advanced,

inflammatory, or arly stage breast cancer (either greater than 2 cm in diameter or

node positive) as part of a complete treatment regimen for early breast cancer.

This indication is based on demonstration of an improvement in pathological

complete response rate. No data are available demonstrating improvement in

event-free survival or overall.

Perjeta is indicated for use in combination with trastuzumab and chemotherapy for

the adjuvant treatment of patients with HER2-positive early breast cancer at high

risk of recurrence (positive nodes).

:רבסה

יתחת וק םע טסקט

.ןולעל ףסוהש טסקט ןייצמ

הצוח וק םע טסקט

.ןולעה ןמ רסוהש טסקט ןייצמ

.תואירבה דרשמ י"ע רשואש יפכ אפורל ןולעב ןייעל שי ףסונ עדימל

ןכדועמה ןולעה

חלשנ

לבקל ןתינו ,תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל

ספדומ י"ע שור :םושירה לעבל היינפ

ד.ת ,מ"עב )לארשי( הקיטבצמרפ

6391

ןורשה דוה ,

4524079

ןופלט

09-9737777

:טנרטניאב ונתבותכ .

www.roche.co.il

טורבסיו לטיבא

רדא יליל

םושיר תקלחמ

הנוממ תחקור

Page 2 of 2

Perjeta

Vials 420mg/14ml

אפורל ןולעב םייתוהמ םינוכדע

ףיעסב

Special warnings and precautions for use

4.4

אבה עדימה ןכדוע

:

Infusion reactions

Perjeta has been associated with infusion reactions, including events with a fatal outcome

(see section 4.8). Close observation of the patient during and for 60 minutes after the first

infusion and during and for 30-60 minutes after subsequent infusions of Perjeta is

recommended. If a significant infusion reaction occurs, the infusion should be slowed down

or interrupted and appropriate medical therapies should be administered. Patients should

be evaluated and carefully monitored until complete resolution of signs and symptoms.

Permanent discontinuation should be considered in patients with severe infusion reactions.

This clinical assessment should be based on the severity of the preceding reaction and

response to administered treatment for the adverse reaction

Hypersensitivity reactions/anaphylaxis

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity,

including anaphylaxis and events with a fatal outcome, has been observed in clinical trials

with Perjeta (see section 4.8). Medicinal products to treat such reactions, as well as

emergency equipment, should be available for immediate use. Perjeta must be permanently

discontinued in case of NCI-CTCAE Grade 4 hypersensitivity reactions (anaphylaxis),

bronchospasm or acute respiratory distress syndrome

ףיעסב

4.8 Undesirable effects

אבה עדימה ןכדוע

:

Table 2 Summary of ADRs in patients treated with Perjeta in clinical trials, and in the

Post-marketing setting

[…]

* ADRs with a fatal outcome have been reported.

** For the overall treatment period across the 4 studies. The incidence of left ventricular

dysfunction and cardiac failure congestive reflect the MedDRA Preferred Terms reported in

the individual studies.

° Hypersensitivity/anaphylactic reaction is based on a group of terms.

°° Infusion reaction includes a range of different terms within a time window, see “Description

of selected adverse reactions” below.

† ADRs reported in the post marketing setting-

Ref: EMEA/H/C/PSUSA/00010125/201806 (April 2019) 1 Perjeta PI_Ver 6.0

Perjeta_PI_Ver 6.0

Perjeta

®

PERTUZUMAB

Concentrate for solution for infusion

1.

NAME OF THE MEDICINAL PRODUCT

Perjeta 420 mg concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One 14 ml vial of concentrate contains 420 mg of pertuzumab at a concentration of 30 mg/ml.

After dilution, one ml of solution contains approximately 3.02 mg of pertuzumab for the initial dose and

approximately 1.59 mg of pertuzumab for the maintenance dose (see section 6.6).

Pertuzumab is a humanised IgG1 monoclonal antibody produced in mammalian (Chinese hamster ovary)

cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear to slightly opalescent, colourless to pale yellow, liquid.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Early breast cancer

Perjeta is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment

of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater

than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.

Perjeta is indicated for use in combination with trastuzumab and chemotherapy for the adjuvant treatment of

patients with HER2-positive early breast cancer at high risk of recurrence (positive nodes).

Metastatic Breast Cancer

Perjeta is indicated in combination with trastuzumab and docetaxel for the treatment of patients with HER2

positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for

metastatic disease.

4.2

Posology and method of administration

Perjeta should only be initiated under the supervision of a physician experienced in the administration of

anti-cancer agents. Perjeta should be administered by a healthcare professional prepared to manage

anaphylaxis and in an environment where full resuscitation facilities are immediately available.

Posology

Patients treated with Perjeta must have HER2-positive tumour status, defined as a score of 3+ by

immunohistochemistry (IHC) and/or a ratio of ≥ 2.0 by in situ hybridisation (ISH) assessed by a validated

test.

To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which

can ensure validation of the testing procedures. For full instructions on assay performance and interpretation

please refer to the package leaflets of validated HER2 testing assays.

The recommended initial loading dose of pertuzumab is 840 mg administered as a 60 minute intravenous

infusion, followed every 3 weeks thereafter by a maintenance dose of 420 mg administered over a period of

30 to 60 minutes. An observation period of 30 - 60 minutes is recommended after completion of each

infusion. The observation period should be completed prior to any subsequent infusion of trastuzumab or

chemotherapy (see section 4.4).

Perjeta and trastuzumab should be administered sequentially and not mixed in the same infusion bag. Perjeta

and trastuzumab can be given in any order. When administered with Perjeta the

recommendation is to follow a 3 weekly schedule for trastuzumab administered as either:

an IV infusion with an initial loading dose of trastuzumab 8 mg/kg body weight followed every 3 weeks

thereafter by a maintenance dose of 6 mg/kg body weight

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

patient’s body weight.

In patients receiving a taxane, Perjeta and trastuzumab should be administered prior to the taxane.

When administered with Perjeta, docetaxel can be started at 75 mg/m2, and subsequently escalated to 100

mg/m2 depending on the chosen regimen and tolerability of the initial dose. Alternatively, docetaxel can be

given at 100 mg/m2 on a 3 weekly schedule from the start, again depending on the chosen regimen. If a

carboplatin-based regimen is used, the recommended dose for docetaxel is 75 mg/m2 throughout (no dose

escalation). When administered with Perjeta in the adjuvant setting, the recommended dose of paclitaxel is

80 mg/m2 once weekly for 12 weekly cycles.

In patients receiving an anthracycline-based regimen, Perjeta and trastuzumab should be administered

following completion of the entire anthracycline regimen (see section 4.4).

Metastatic breast cancer

Perjeta should be administered in combination with trastuzumab and docetaxel . Treatment with Perjeta and

trastuzumab may continue until disease progression or unmanageable toxicity even if treatment with

docetaxel is discontinued.

Early breast cancer

In the neoadjuvant setting, Perjeta should be administered for 3 to 6 cycles in combination with trastuzumab

and chemotherapy, as part of a complete treatment regimen for early breast cancer (see section 5.1).

In the adjuvant setting, Perjeta should be administered in combination with trastuzumab for a total of one

year (up to 18 cycles or until disease recurrence, or unmanageable toxicity, whichever occurs first) as part of

a complete regimen for early breast cancer and regardless of the timing of surgery. Treatment should include

standard anthracycline- and/or taxane-based chemotherapy. Perjeta and trastuzumab should start on Day 1 of

the first taxane-containing cycle and should continue even if chemotherapy is discontinued.

Delayed or missed doses

For recommendations on delayed or missed doses, please refer to Table 1 below.

Table 1

Recommendations regarding delayed or missed doses

Time between two

sequential

infusions

Perjeta

trastuzumab

IV

SC

< 6 weeks

The 420 mg dose of

pertuzumab should be

administered as soon as

possible. Do not wait

until the next planned

dose. Thereafter, revert to

the original planned

schedule.

The 6 mg/kg dose of

trastuzumab IV should

be administered as soon

as possible. Do not wait

until the next planned

dose. Thereafter, revert

to the original planned

schedule.

The fixed dose of

600mg trastuzumab

SC should be

administered as soon

as possible.

Do not wait until the

next planned dose.

6 weeks

The 840 mg loading dose

of pertuzumab should be

re-administered as a 60

minute infusion, followed

by a maintenance dose of

420 mg IV administered

every 3 weeks thereafter.

The loading dose of

8 mg/kg of trastuzumab

IV should be re-

administered over

approximately

90 minutes, followed by

a maintenance dose of

6 mg/kg IV administered

every 3 weeks thereafter.

Dose modification

Dose reductions are not recommended for Perjeta or trastuzumab. For details regarding trastuzumab, please

refer to the Prescribing Information.

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 presecribing information.

If trastuzumab treatment is discontinued, treatment with Perjeta should be discontinued.

Left ventricular dysfunction

Perjeta and trastuzumab should be withheld for at least 3 weeks for any signs and symptoms suggestive of

congestive heart failure. Perjeta should be discontinued if symptomatic heart failure is confirmed (see section

4.4 for more details).

Patients with metastatic breast cancer

Patients should have a pre-treatment left ventricular ejection fraction (LVEF) of ≥ 50%. Perjeta and

trastuzumab should be withheld for at least 3 weeks for:

a drop in LVEF to less than 40%

a LVEF of 40%-45% associated with a fall of ≥ 10% points below pre-treatment value.

Perjeta and trastuzumab may be resumed if the LVEF has recovered to > 45% or to 40-45% associated with a

difference of < 10% points below pre-treatment values.

Patients with early breast cancer

Patients should have a pre-treatment LVEF of ≥ 55% (≥ 50% after completion of the anthracycline

component of chemotherapy, if given). Perjeta and trastuzumab should be withheld for at least 3 weeks for:

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

Perjeta and trastuzumab may be resumed if the LVEF has recovered to ≥50% or to a difference of < 10%

points below pre-treatment values.

Elderly patients

No overall differences in efficacy and safety of Perjeta were observed in patients ≥65 and <65 years of age

with the exception of grade 3-4 diarrhoea (6.8% higher) and all grade of intensity decreased appetite (13%

higher), weight decreased (7% higher), asthenia (7% higher), and hypomagnesemia (5% higher), which had

an increased incidence in patients ≥65 years of age. No dose adjustment is necessary in the elderly

population ≥ 65 years of age. Limited data are available in patients > 75 years of age.

Renal impairment

Dose adjustments of pertuzumab are not needed in patients with mild or moderate renal impairment. No dose

recommendations can be made for patients with severe renal impairment because of the limited

pharmacokinetic data available (see section 5.2).

Hepatic impairment

The safety and efficacy of Perjeta have not been studied in patients with hepatic impairment. No specific

dose recommendations can be made.

Paediatric population

The safety and efficacy of Perjeta in children and adolescents below 18 years of age have not been

established. There is no relevant use of Perjeta in the paediatric population in the indication of breast cancer.

Method of administration

Perjeta is administered intravenously by infusion. It should not be administered as an intravenous push or

bolus. For instructions on dilution of Perjeta prior to administration, see sections 6.2 and 6.6.

For the initial dose, the recommended infusion period is 60 minutes. If the first infusion is well tolerated,

subsequent infusions may be administered over a period of 30 minutes to 60 minutes (see section 4.4).

Infusion reactions

The infusion rate may be slowed or interrupted if the patient develops an infusion reaction (see section 4.8).

The infusion may be resumed when symptoms abate. Treatment including oxygen, beta agonists,

antihistamines, rapid i.v. fluids and antipyretics may also help alleviate symptoms.

Hypersensitivity reactions/anaphylaxis

The infusion should be discontinued immediately and permanently if the patient experiences a NCI-CTCAE

Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.4).

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the

administered product should be clearly recorded.

Left ventricular dysfunction (including congestive heart failure)

Decreases in LVEF have been reported with medicinal products that block HER2 activity, including Perjeta.

The incidence of symptomatic left ventricular systolic dysfunction (LVD) [congestive heart failure] was

higher in patients treated with Perjeta in combination with trastuzumab and chemotherapy compared with

trastuzumab and chemotherapy . Patients who have received prior anthracyclines or prior radiotherapy to the

chest area may be at higher risk of LVEF declines. The majority of cases of symptomatic heart failure

reported in the adjuvant setting were in patients who received anthracycline-based chemotherapy (see section

4.8).

Perjeta has not been studied in patients with: a pre-treatment LVEF value of < 50%; a prior history of

congestive heart failure (CHF); LVEF declines to < 50% during prior trastuzumab adjuvant therapy; or

conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial

infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure

to > 360 mg/m

of doxorubicin or its equivalent.

Assess LVEF prior to initiation of Perjeta and at regular intervals during treatment with Perjeta (e.g. once

during neoadjuvant treatment and every 12 weeks in the adjuvant or metastatic setting) to ensure that LVEF

is within normal limits. If the LVEF has declined as indicated in section 4.2 and has not improved, or has

declined further at the subsequent assessment, discontinuation of Perjeta and trastuzumab should be strongly

considered, unless the benefits for the individual patient are deemed to outweigh the risks.

Cardiac risk should be carefully considered and balanced against the medical need of the individual patient

before use of Perjeta with an anthracycline. Based on the pharmacological actions of

HER2-targeted agents and anthracyclines, the risk of cardiac toxicity might be expected to be higher with

concomitant use of Perjeta and anthracyclines than with sequential use.

Sequential use of Perjeta (in combination with trastuzumab and a taxane) has been evaluated following the

epirubicin or doxorubicin component of many anthracycline-based regimens in the APHINITY and

BERENICE studies. However, only limited safety data are available on concurrent use of Perjeta and an

anthracycline. In the TRYPHAENA study, Perjeta was given concurrently with epirubicin, as part of the

FEC (5-fluorouracil, epirubicin, cyclophosphamide) regimen (see sections 4.8 and 5.1). Only chemotherapy-

naive patients were treated and they received low cumulative doses of epirubicin (up to 300 mg/m

). In this

study, cardiac safety was similar to that observed in patients given the same regimen but with Perjeta

administered sequentially (following FEC chemotherapy).

Infusion reactions

Perjeta has been associated with infusion reactions, including events with a fatal outcome (see section 4.8).

Close observation of the patient during and for 60 minutes after the first infusion and during and for 30-60

minutes after subsequent infusions of Perjeta is recommended. If a significant infusion reaction occurs, the

infusion should be slowed down or interrupted and appropriate medical therapies should be administered.

Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms.

Permanent discontinuation should be considered in patients with severe infusion reactions. This clinical

assessment should be based on the severity of the preceding reaction and response to administered treatment

for the adverse reaction (see section 4.2).

Hypersensitivity reactions/anaphylaxis

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including

anaphylaxis and events with a fatal outcome, has been observed with Perjeta (see section 4.8). Medicinal

products to treat such reactions, as well as emergency equipment, should be available for immediate use.

Perjeta must be permanently discontinued in case of NCI-CTCAE Grade 4 hypersensitivity reactions

(anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.2).

Febrile neutropenia

Patients treated with Perjeta, trastuzumab and docetaxel are at increased risk of febrile neutropenia compared

with patients treated with placebo, trastuzumab and docetaxel, especially during the first 3 cycles of

treatment (see section 4.8). In the CLEOPATRA trial in metastatic breast cancer, nadir neutrophil counts

were similar in Perjeta-treated and placebo-treated patients. The higher incidence of febrile neutropenia in

Perjeta-treated patients was associated with the higher incidence of mucositis and diarrhoea in these patients.

Symptomatic treatment for mucositis and diarrhoea should be considered. No events of febrile neutropenia

were reported after cessation of docetaxel.

Diarrhoea

Perjeta may elicit severe diarrhoea. Diarrhoea is most frequent during concurrent administration with taxane

therapy. Elderly patients (> 65 years) may have a higher risk of diarrhoea compared with younger patients (<

65 years). Treat diarrhoea according to standard practice and guidelines. Early intervention with loperamide,

fluids and electrolyte replacement should be considered, particularly in elderly patients, and in case of severe

or prolonged diarrhoea. Interruption of treatment with pertuzumab should be considered if no improvement

in the patient’s condition is achieved. When the diarrhoea is under control treatment with pertuzumab may be

reinstated.

4.5

Interaction with other medicinal products and other forms of interaction

No pharmacokinetic (PK) interactions were observed between pertuzumab and trastuzumab, or between

pertuzumab and docetaxel in a sub-study of 37 patients in the randomised, pivotal trial CLEOPATRA in

metastatic breast cancer. In addition, in the population PK analysis, no evidence of a drug-drug interaction

has been shown between pertuzumab and trastuzumab or between pertuzumab and docetaxel. This absence

of drug-drug interaction was confirmed by pharmacokinetic data from the NEOSPHERE and APHINITY

studies.

Five studies evaluated the effects of pertuzumab on the PK of co-administered cytotoxic agents, docetaxel,

paclitaxel, gemcitabine, capecitabine, carboplatin and erlotinib. There was no evidence of any PK interaction

between pertuzumab and any of these agents. The PK of pertuzumab in these studies was comparable to

those observed in single-agent studies.

4.6

Fertility, pregnancy and lactation

Contraception

Women of childbearing potential should use effective contraception while receiving Perjeta and for 6 months

following the last dose of pertuzumab.

Pregnancy

There is limited amount of data from the use of pertuzumab in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Perjeta is not recommended during pregnancy and in women of childbearing potential not using

contraception.

Breast-feeding

Because human IgG is secreted in human milk and the potential for absorption and harm to the infant is

unknown, a decision should be made to discontinue breast-feeding or to discontinue treatment, taking into

account the benefit of breast-feeding for the child and the benefit of Perjeta therapy for the woman (see

section 5.2).

Fertility

No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. In repeated

dose toxicity studies in cynomolgus monkeys, no definitive conclusions could be drawn on the adverse effect

on male reproductive organs. No adverse reactions were observed in sexually mature female cynomolgus

monkeys exposed to pertuzumab (see section 5.3).

4.7

Effects on ability to drive and use machines

On the basis of reported adverse reactions, Perjeta has no or negligible influence on the ability to drive or use

machines. Patients experiencing infusion reactions should be advised not to drive and use machines until

symptoms abate.

4.8

Undesirable effects

Summary of the safety profile

The safety of Perjeta has been evaluated in more than 6,000 patients in Phase I, II, and III trials in patients

with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic

agents. Those studies included the pivotal trials CLEOPATRA (n=808), NEOSPHERE (n=417),

TRYPHAENA (n=225), and APHINITY (n=4804) [pooled in Table 2]. The safety of Perjeta was generally

consistent across studies, although the incidence and most common adverse drug reactions (ADRs) varied

depending on whether Perjeta was administered as monotherapy or with concomitant anti-neoplastic agents.

Tabulated list of adverse reactions

Table 2 summarizes the ADRs from the Perjeta-treated groups of the following pivotal clinical trials:

CLEOPATRA, in which Perjeta was given in combination with docetaxel and trastuzumab to

patients with metastatic breast cancer (n=453)

NEOSPHERE (n=309) and TRYPHAENA (n=218), in which neoadjuvant Perjeta was given in

combination with trastuzumab and chemotherapy to patients with locally advanced, inflammatory, or

early breast cancer

APHINITY, in which adjuvant Perjeta was given in combination with trastuzumab and

anthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patients with

early breast cancer (n=2364)

In addition, ADRs reported in the post-marketing setting are included in Table 2. As Perjeta was used with

trastuzumab and chemotherapy in these trials, it is difficult to ascertain the causal relationship of an adverse

event to a particular medicinal product.

The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon( ≥ 1/1,000 to < 1/100)

Rare (≥ 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

Within each frequency grouping and SOC, ADRs are presented in the order of decreasing seriousness.

The most common ADRs (≥30%) from this pooled data were diarrhoea, alopecia, nausea, fatigue,

neutropenia, and vomiting. The most common NCI-CTCAE Grade 3-4 ADRs (≥10%) were neutropenia and

febrile neutropenia.

Table 2

Summary of ADRs in patients treated with Perjeta in clinical trials^, and in the Post-

marketing setting

System organ class

Very Common

Common

Uncommon

Rare

Infections and infestations

Nasopharyngitis

Paronychia

Upper respiratory tract

infection

Blood and lymphatic

system

disorders

Febrile neutropenia*

Neutropenia

Leucopenia

Anaemia

Immune system disorders

Infusion reaction°°, *

Hypersensitivity°, *

Drug hypersensitivity°,

Anaphylactic reaction°,

Cytokine release

syndrome°°

Metabolism and nutrition

disorders

Decreased appetite

Tumour lysis

syndrome†

Psychiatric disorders

Insomnia

Nervous system disorders

Neuropathy peripheral

Headache

Dysgeusia

Peripheral sensory

neuropathy

Dizziness

Paraesthesia

Eye disorders

Lacrimation increased

Cardiac disorders

Left ventricular

dysfunction **

Cardiac failure

congestive**

Vascular disorders

Hot flush

Respiratory, thoracic and

mediastinal disorders

Cough

Epistaxis

Dyspnoea

Interstitial lung disease

Pleural effusion

Gastrointestinal disorders

Diarrhoea

Vomiting

Stomatitis

Nausea

Constipation

Dyspepsia

Abdominal pain

Skin and subcutaneous

tissue disorders

Alopecia

Rash

Nail disorder

Pruritus

Dry skin

Musculoskeletal and

connective tissue disorders

Myalgia

Arthralgia

Pain in extremity

System organ class

Very Common

Common

Uncommon

Rare

General disorders and

administration site

conditions

Mucosal inflammation

Oedema peripheral

Pyrexia

Fatigue

Asthenia

Chills

Pain

Oedema

^

Table 2 shows pooled data from the overall treatment period in CLEOPATRA (data cutoff 11 February 2014; median

number of cycles of Perjeta was 24); and from the neoadjuvant treatment period in NEOSPHERE (median number of

cycles of Perjeta was 4, across all treatment arms) and TRYPHAENA (median number of cycles of Perjeta was 3 – 6

across treatment arms) and from the treatment period of APHINITY (median number of cycles of Perjeta was 18).

* ADRs with a fatal outcome have been reported.

** For the overall treatment period across the 4 studies. The incidence of left ventricular dysfunction and cardiac failure

congestive reflect the MedDRA Preferred Terms reported in the individual studies.

° Hypersensitivity/anaphylactic reaction is based on a group of terms.

°° Infusion reaction includes a range of different terms within a time window, see “Description of selected adverse

reactions” below.

† ADRs reported in the post marketing setting

Description of selected adverse reactions

Left ventricular dysfunction (LVD)

In the pivotal trial CLEOPATRA in metastatic breast cancer, the incidence of LVD during study treatment

was higher in the placebo-treated group than in the Perjeta-treated group (8.6% and 6.6%, respectively). The

incidence of symptomatic LVD was also lower in the Perjeta-treated group (1.8% in the placebo-treated group

vs. 1.5% in the Perjeta-treated group) (see section 4.4).

In the neoadjuvant trial NEOSPHERE, in which patients received 4 cycles of Perjeta as neoadjuvant treatment,

the incidence of LVD (during the overall treatment period) was higher in the Perjeta, trastuzumab and

docetaxel-treated group (7.5%) compared to the trastuzumab and docetaxel-treated group (1.9%). There was

one case of symptomatic LVD in the Perjeta and trastuzumab-treated group.

In the neoadjuvant trial TRYPHAENA, the incidence of LVD (during the overall treatment period) was 8.3%

in the group treated with Perjeta plus trastuzumab and FEC (5-fluorouracil, epirubicin, cyclophosphamide)

followed by Perjeta plus trastuzumab and docetaxel; 9.3% in the group treated with Perjeta plus trastuzumab

and docetaxel following FEC; and 6.6% in the group treated with Perjeta in combination with TCH (docetaxel,

carboplatin and trastuzumab). The incidence of symptomatic LVD (congestive heart failure) was 1.3% in the

group treated with Perjeta plus trastuzumab and docetaxel following FEC (this excludes a patient who

experienced symptomatic LVD during FEC treatment prior to receiving Perjeta plus trastuzumab and

docetaxel) and also 1.3% in the group treated with Perjeta in combination with TCH. No patients in the group

treated with Perjeta plus trastuzumab and FEC followed by Perjeta plus trastuzumab and docetaxel experienced

symptomatic LVD.

In the neoadjuvant period of the BERENICE trial, the incidence of NYHA Class III/IV symptomatic LVD

(congestive heart failure according to NCI-CTCAE v.4) was 1.5% in the group treated with dose dense

doxorubicin and cyclophosphamide (AC) followed by Perjeta plus trastuzumab and paclitaxel and none of

the patients (0%) experienced symptomatic LVD in the group treated with FEC followed by Perjeta in

combination with trastuzumab and docetaxel. The incidence of asymptomatic LVD (ejection fraction

decrease according to NCI-CTCAE v.4) was 7% in the group treated with dose dense AC followed by

Perjeta plus trastuzumab and paclitaxel and 3.5% in the group treated with FEC followed by Perjeta plus

trastuzumab and docetaxel.

In APHINITY, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEF decline of at

least 10% points from baseline and to <50% was <1% (0.6% of Perjeta-treated patients vs 0.3% of placebo-

treated patients). Of the patients who experienced symptomatic heart failure, 46.7% of Perjeta-treated patients

and 57.1% of placebo-treated patients had recovered (defined as 2 consecutive LVEF measurements above

50%) at the data cutoff. The majority of the events were reported in anthracycline-treated patients.

Asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10% points from baseline

and to <50% were reported in 2.7% of Perjeta-treated patients and 2.8% of placebo-treated patients, of whom

79.7% of Perjeta-treated patients and 80.6% of placebo-treated patients had recovered at the data cutoff.

Infusion reactions

An infusion reaction was defined in the pivotal trials as any event reported as hypersensitivity, anaphylactic

reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same

day as the infusion. In the pivotal trial CLEOPATRA, the initial dose of Perjeta was given the day before

trastuzumab and docetaxel to allow for the examination of Perjeta-associated reactions. On the first day

when only Perjeta was administered, the overall frequency of infusion reactions was 9.8% in the placebo-

treated group and 13.2% in the Perjeta-treated group, with the majority of infusion reactions being mild or

moderate. The most common infusion reactions (≥ 1.0%) in the Perjeta-treated group were pyrexia, chills,

fatigue, headache, asthenia, hypersensitivity and vomiting.

During the second cycle when all medicinal products were administered on the same day, the most common

infusion reactions in the Perjeta-treated group (≥ 1.0%) were fatigue, dysgeusia, drug hypersensitivity,

myalgia and vomiting (see section 4.4).

In neoadjuvant and adjuvant trials, Perjeta was administered on the same day as other study treatments in all

cycles. Infusion reactions occurred in 18.6% - 25.0% of patients on the first day of Perjeta administration (in

combination with trastuzumab and chemotherapy). The type and severity of events were consistent with

those observed in CLEOPATRA at the cycles when Perjeta was given on the same day as trastuzumab and

docetaxel, with the majority of reactions being mild or moderate in severity.

Hypersensitivity reactions/anaphylaxis

In the pivotal trial CLEOPATRA in metastatic breast cancer, the overall frequency of investigator reported

hypersensitivity/anaphylaxis events during the entire treatment period was 9.3% in the placebo-treated group

and 11.3% in the Perjeta-treated group, of which 2.5% and 2.0% were

NCI-CTCAE Grade 3-4, respectively. Overall, 2 patients in the placebo-treated group and 4 patients in the

Perjeta-treated group experienced events described as anaphylaxis by the investigator (see section 4.4).

Overall, the majority of hypersensitivity reactions were mild or moderate in severity and resolved upon

treatment. Based on modifications made to the study treatment, most reactions were assessed as secondary to

docetaxel infusions.

In the neoadjuvant and adjuvant trials, hypersensitivity/anaphylaxis events were consistent with those

observed in CLEOPATRA. In NEOSPHERE, two patients in the Perjeta and docetaxel-treated group

experienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overall frequency of

hypersensitivity/anaphylaxis was highest in the Perjeta and TCH treated group (13.2% and 7.6%,

respectively), of which 2.6% and 1.3% of events, respectively, were NCI-CTCAE Grade 3-4.

Febrile neutropenia

In the pivotal trial CLEOPATRA, the majority of patients in both treatment groups experienced at least one

leucopenic event (63.0% of patients in the Perjeta-treated group and 58.3% of patients in the placebo-treated

group), of which the majority were neutropenic events (see section 4.4). Febrile neutropenia occurred in

13.7% of Perjeta-treated patients and 7.6% of placebo-treated patients. In both treatment groups, the

proportion of patients experiencing febrile neutropenia was highest in the first cycle of therapy and declined

steadily thereafter. An increased incidence of febrile neutropenia was observed among Asian patients in both

treatment groups compared with patients of other races and from other geographic regions. Among Asian

patients, the incidence of febrile neutropenia was higher in the Perjeta-treated group (25.8%) compared with

the placebo-treated group (11.3%).

In the NEOSPHERE trial, 8.4% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel

experienced febrile neutropenia compared with 7.5% of patients treated with trastuzumab and docetaxel. In

the TRYPHAENA trial, febrile neutropenia occurred in 17.1% of patients treated with neoadjuvant Perjeta +

TCH, and 9.3% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel following FEC. In

TRYPHAENA, the incidence of febrile neutropenia was higher in patients who received six cycles of Perjeta

compared with patients who received three cycles of Perjeta, independent of the chemotherapy given. As in

the CLEOPATRA trial, a higher incidence of neutropenia and febrile neutropenia was observed among

Asian patients compared with other patients in both neoadjuvant trials. In NEOSPHERE, 8.3% of Asian

patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel experienced febrile neutropenia

compared with 4.0% of Asian patients treated with neoadjuvant trastuzumab and docetaxel.