Perjeta 420 mg Concentrate for Solution for Infusion

CDS safety update

CDS safety Update

 Updates to Sections 4.4 and 4.8 to reflect the label change on hypersensitivity reactions or immune related reactions (HSR/IRR).

4.8       Undesirable effects

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II trials conducted in patients with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic agents. The safety of Perjeta in Phase I and II studies (including the BERENICE trial) was generally consistent with that observed in the CLEOPATRA, NEOSPHERE and TRYPHAENA trials (pooled in table 1), 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.

Metastatic Breast Cancer

In the pivotal clinical trial CLEOPATRA, 408 patients received at least one dose of Perjeta in combination with trastuzumab and docetaxel. The most common ADRs (≥ 50%) seen with Perjeta in combination with trastuzumab and docetaxel were diarrhoea, alopecia and neutropenia. The most common NCI-CTCAE  v.3 Grade 3-4 ADRs (> 10%) were neutropenia, febrile neutropenia and leucopenia, and the most common serious adverse events were febrile neutropenia, neutropenia and diarrhoea. Treatment-related deaths occurred in 1.2% of patients in the Perjeta-treated group and 1.5% of patients in the placebo-treated group and were mainly due to febrile neutropenia and/or infection.  

In the pivotal trial CLEOPATRA, ADRs were reported less frequently after discontinuation of docetaxel treatment. After discontinuation of docetaxel, ADRs in the Perjeta and trastuzumab treated group occurred in < 10% of patients with the exception of diarrhoea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), nasopharyngitis (17.0%), asthenia (13.4%), pruritus (13.7%), arthralgia (11.4%), nausea (12.7%), pain in extremity (13.4%), back pain (12.1%) and cough (12.1%).

Neoadjuvant Treatment of Breast Cancer

In the neoadjuvant trial NEOSPHERE, the most common ADRs (≥50%) seen with Perjeta in combination with trastuzumab and docetaxel were alopecia and neutropenia. The most common NCI-CTCAE v.3 Grade 3-4 ADR (≥10%) was neutropenia.

In the neoadjuvant trial TRYPHAENA, when Perjeta was administered in combination with trastuzumab and FEC (5-fluorouracil, epirubicin, cyclophosphamide) for 3 cycles followed by 3 cycles of Perjeta, trastuzumab and docetaxel, the most common ADRs (≥50%) were neutropenia, diarrhoea and nausea. The most common NCI-CTCAE v.3 Grade 3-4 ADRs (≥10%) were neutropenia, febrile neutropenia and leucopenia. When Perjeta was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC (5-fluorouracil, epirubicin, cyclophosphamide), the most common ADRs (≥50%) were diarrhoea, nausea and alopecia. The most common NCI-CTCAE v.3 Grade 3-4 ADRs (≥10%) were neutropenia and leucopenia. Similarly, when Perjeta was administered in combination with TCH (docetaxel, carboplatin and trastuzumab) for 6 cycles, the most common ADRs (≥50%) were diarrhoea and alopecia. The most common NCI-CTCAE v.3 Grade 3-4 ADRs (≥10%) were neutropenia, febrile neutropenia, anaemia, leucopenia and diarrhoea. The safety of Perjeta administered for more than 6 cycles in the neoadjuvant setting has not been established.

In the BERENICE trial, when Perjeta was administered in combination with trastuzumab and paclitaxel for four cycles following four cycles of two weekly doxorubicin and cyclophosphamide (dose dense AC), the most common ADRs (≥50%) were nausea, diarrhoea, fatigue and alopecia. The most common NCI-CTCAE (v.4) Grade 3-4 ADR (≥10%) was neutropenia. When Perjeta was administered in combination with trastuzumab and docetaxel for four cycles following four cycles of FEC the most common ADRs (≥50%) were nausea, diarrhea and alopecia. The most common NCI-CTCAE (v.4)  Grade 3-4 ADRs (≥10%) were febrile neutropenia and diarrhoea. The overall safety profile seen in BERENICE is consistent with that observed in previous data in the neoadjuvant setting for NEOSPHERE and TRYPHAENA.

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The infusion should be discontinued immediately and permanently if the patient experiences a NCI-CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.4).

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4.4       Special warnings and precautions for use

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In the neoadjuvant period of NEOSPHERE, the incidence of LVD was higher in the Perjeta–treated groups than in those who did not receive Perjeta. An increased incidence of LVEF declines was also observed in patients treated with Perjeta in combination with trastuzumab and docetaxel; LVEF recovered to ≥50% in all patients.  Findings were similar in other neoadjuvant trials (see section 5.1).

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Cardiac risk should be carefully considered and balanced against the medical need of the individual patient before use of Perjeta with an anthracycline. There are limited safety data available from the TRYPHAENA study concerning sequential or concomitant administration of Perjeta with epirubicin, as part of the FEC regimen (see sections 4.8 and 5.1).  There are no Cardiac safety data from the BERENICE study, in which patients were treated sequentially with either epirubicsin or doxorubicin followed by available concerning use of Perjeta and trastuzumab with doxorubicin, were consistent with previous data in the neoadjuvant setting (see section 4.8).

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4.8       Undesirable effects

Summary of the safety profile

The safety of Perjeta has been evaluated in more than 1,6002,000 patients in the randomized trials CLEOPATRA (n=808), NEOSPHERE (n=417), and TRYPHAENA (n=225) and in Phase I and phase II trials conducted in patients with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic agents. The safety of Perjeta in Phase I and II studies (including the BERENICE trial) was generally consistent with that observed in the CLEOPATRA, NEOSPHERE and TRYPHAENA trials (pooled in table 1), 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.

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In the BERENICE trial, when Perjeta was administered in combination with trastuzumab and paclitaxel for four cycles following four cycles of two weekly doxorubicin and cyclophosphamide (dose dense AC), the most common ADRs (≥50%) were nausea, diarrhoea, fatigue and alopecia. The most common NCI-CTCAE (v.4) Grade 3-4 ADR (≥10%) was neutropenia. When Perjeta was administered in combination with trastuzumab and docetaxel for four cycles following four cycles of FEC the most common ADRs (≥50%) were nausea, diarrhea and alopecia. The most common NCI-CTCAE (v.4)  Grade 3-4 ADRs (≥10%) were febrile neutropenia and diarrhoea. The overall safety profile seen in BERENICE is consistent with that observed in previous data in the neoadjuvant setting for NEOSPHERE and TRYPHAENA.

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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 doxorubin 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.

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5.1       Pharmacodynamic properties

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BERENICE (WO29217)

BERENICE is a non-randomized, open-label, multicentre, multinational, Phase II trial conducted in 401 patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (with primary tumours > 2cm in diameter or node‑positive disease).

The BERENICE study included two parallel groups of patients. Patients considered suitable for neoadjuvant treatment with trastuzumab plus anthracycline/taxane-based chemotherapy were allocated to receive one of the two following regimens prior to surgery as follows:

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

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

Following surgery all patients received Perjeta and trastuzumab intravenously every 3 weeks to complete 1 year of therapy.

The primary endpoint of the BERENICE trial is cardiac safety in the neoadjuvant period of the trial. The primary endpoint of cardiac safety, i.e. the incidence of NYHA Class III/IV LVD and LVEF declines, was consistent with previous data in the neoadjuvant setting (see section 4.4. and 4.8).

Immunogenicity

Patients in the pivotal trial CLEOPATRA were tested at multiple time-points for anti-therapeuticdrug antibodies (ATAADA) to Perjeta. Approximately 2.83.3% (1113/386 389 patients) of Perjeta-treated patients and 6.27% (2325/372 patients) of placebo-treated patients tested positive for ADTAs. Of these 34 38 patients, none experienced severe (NCI-CTCAE Grade 4) infusion or hypersensitivity reactions (anaphylaxis) that were clearly related to ADTA. In the neadjuvant part of the BERENICE trial, 0.3% (1/383) of the patients treated with Perjeta tested positive for ADA.  This patient did not experience any anaphylactic or hypersensitivity reactions. However, Grade 3 hypersensitivity reactions associated with detectable ATAs ADAs occurred in 2 of 366 (0.5%) Perjeta-treated patients (0.5%) in phase I and II studies. There are currently insufficient data to evaluate the effects of ATA ADA on the efficacy of Perjeta in combination with trastuzumab and docetaxel.

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4.4       Special warnings and precautions for use

Diarrhoea

Pertuzumab may elicit severe diarrhoea. In case of onset of severe diarrhoea an anti-diarrhoeal treatment should be instituted and interruption of the treatment with pertuzumab should be considered if no improvement of the condition is achieved. When the diarrhoea is under control the treatment with pertuzumab may be reinstated.

10.       DATE OF REVISION OF THE TEXT

18 September 2015

Underlined text has been added, text with strike-through deleted:

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 3.36 3.02 mg of pertuzumab for the initial dose and approximately 1.68 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.

4.1          Therapeutic indications

Metastatic Breast Cancer

Perjeta is indicated for use in combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

Neoadjuvant Treatment of Breast Cancer

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

4.2          Posology and method of administration

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When administered with Perjeta the recommended initial dose of docetaxel is 75 mg/m², administered thereafter on a 3 weekly schedule. The dose of docetaxel may be escalated to 100 mg/m² on subsequent cycles if the initial dose is well tolerated (the docetaxel dose should not be escalated when used in combination with carboplatin, trastuzumab and Perjeta).

The medicinal products should be administered sequentially and not mixed in the same infusion bag. Perjeta and trastuzumab can be given in any order. When the patient is receiving docetaxel, this should be administered after Perjeta and trastuzumab. An observation period of 30 to 60 minutes is recommended after each Perjeta infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel (see section 4.4).

Metastatic Breast Cancer

Patients should be treated with Perjeta and trastuzumab until disease progression or unmanageable toxicity.

Neoadjuvant Treatment of Breast Cancer

Perjeta should be administered for 3 to 6 cycles in combination with neoadjuvant trastuzumab and chemotherapy, as part of a treatment regimen for early breast cancer. Following surgery, patients should be treated with adjuvant trastuzumab to complete 1 year of treatment (see section 5.1).

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Dose reductions are not recommended for Perjeta.

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 relevantdocetaxel summary of product characteristics (SmPC).

For trastuzumab, dose reductions are not recommended, see trastuzumab summary of product characteristics (SmPC).

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

If docetaxel is discontinued, treatment with Perjeta and trastuzumab may continue until disease progression or unmanageable toxicity in the metastatic setting.

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Elderly patients

Limited data are available on the safety and efficacy of  Perjetapertuzumab in patients ≥ 65 years of age. No significant differences in safety and efficacy of Perjetapertuzumab were observed between elderly patients aged 65 to 75 years and adult patients aged < 65 years. No dose adjustment is necessary in the elderly population ≥ 65 years of age. Very limited data are available in patients > 75 years of age.

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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 metastatic breast cancer.

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4.4          Special warnings and precautions for use

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Decreases in LVEF have been reported with medicinal products that block HER2 activity, including Perjeta. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines. In the pivotal trial CLEOPATRA in patients with metastatic breast cancer, Perjeta in combination with trastuzumab and docetaxel was not associated with a greater incidence of symptomatic left ventricular systolic dysfunction (LVD) or LVEF declines compared with placebo and trastuzumab and docetaxel (see section 4.8).

In the neoadjuvant setting (NEOSPHERE) the incidence of LVD was higher in the Perjeta–treated groups than in those who did not receive Perjeta. An increased incidence of LVEF declines was also observed in patients treated with Perjeta in combination with trastuzumab and docetaxel; LVEF recovered to ≥50% in all patients.

Perjeta has not been studied in patients with: a pre-treatment LVEF value of ≤ 50%; a prior history of congestive heart failure (CHF); LVEF declines to < 50% during prior trastuzumab adjuvant therapy; or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m² of doxorubicin or its equivalent.

Assess LVEF prior to initiation of Perjeta and every three cycles during treatment with Perjeta (every 3 cycles in the metastatic setting and every 2 cycles  in the neoadjuvant setting) to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40% or 40%-45% associated with ≥ 10% points below the pretreatment value, Perjeta and trastuzumab should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If the LVEF has not improved, or has declined further, discontinuation of Perjeta and trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks (see section 4.2).

Cardiac risk should be carefully considered and balanced against the medical need of the individual patient before use of Perjeta with an anthracycline. There are limited safety data available from the TRYPHAENA study concerning sequential or concomitant administration of Perjeta with epirubicin, as part of the FEC regimen (see sections 4.8 and 5.1). There are no safety data available concerning use of Perjeta with doxorubicin.

Based on the pharmacological actions of pertuzumab and anthracyclines an increased risk of cardiac toxicity might be expected from concomitant use of these agents compared with sequential use, although not seen in the TRYPHAENA study. In this study, only chemotherapy-naive subjects, not receiving additional chemotherapy after surgery, were treated with low cumulative dose of epirubicin, i.e. up to 300 mg/m². 

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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,As nadir neutrophil counts were similar in Perjeta-treated and placebo-treated patients. The, the higher incidence of febrile neutropenia in Perjeta-treated patients wasmay be associated with the higher incidence of mucositis and diarrhoea in these patients. Symptomatic treatment for mucositis and diarrhoea should be considered. NoIn the pivotal trial, CLEOPATRA, no events of febrile neutropenia were reported after cessation of docetaxel.

4.5          Interaction with other medicinal products and other forms of interaction

No pharmacokinetic (PK) interactions were observed between pertuzumabPerjeta and trastuzumab, or between pertuzumabPerjeta 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 pertuzumabPerjeta and trastuzumab  orand between pertuzumabPerjeta and docetaxel. This absence of drug-drug interaction was confirmed by pharmacokinetic data from the NEOSPHERE trial in the neoadjuvant setting.

Four studies have evaluated the effects of pertuzumabPerjeta on the PK of co-administered cytotoxic agents, docetaxel, gemcitabine, erlotinib and capecitabine. There was no evidence of any PK interaction between pertuzumabPerjeta and any of these agents. The PK of pertuzumabPerjeta in these studies was comparable to those observed in single-agent studies.

4.8          Undesirable effects

Summary of the safety profile

The safety of Perjeta has been evaluated in more than 1,600400 patients either in the randomized trialspivotal trial CLEOPATRA (n=808), NEOSPHERE (n=417) and TRYPHAENA (n=225) andor in Phasephase I and phase II trials conducted in patients with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic agents. The safety of Perjeta in Phase I and II studies was generally consistent with that observed in the CLEOPATRA, NEOSPHERE and TRYPHAENA trials, 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.

Metastatic Breast Cancer

In the pivotal clinical trial CLEOPATRA, 408 patients received at least one dose of Perjeta in combination with trastuzumab and docetaxel. The most common adverse drug reactions (ADRs) (≥ 50%) seen with Perjeta in combination with trastuzumab and docetaxel were diarrhoea, alopecia and neutropenia. The most common NCI-CTCAE  v.(version 3) Grade 3-4 ADRs (> 10%) were neutropenia, febrile neutropenia and leucopenia, and the most common serious adverse events were febrile neutropenia, neutropenia and diarrhoea. Treatment-related deaths occurred in 1.2% of patients in the Perjeta-treated group and 1.5% of patients in the placebo-treated group and were mainly due to febrile neutropenia and/or infection.  

In the pivotal trial CLEOPATRA, ADRs were reported less frequently after discontinuation of docetaxel treatment. After discontinuation of docetaxel, ADRs in the Perjeta and trastuzumab treated group occurred in < 10% of patients with the exception of diarrhoea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), nasopharyngitis (17.0%), asthenia (13.4%), pruritus (13.7%), arthralgia (11.4%), nausea (12.7%), pain in extremity (13.4%), back pain (12.1%) and cough (12.1%).

Neoadjuvant Treatment of Breast Cancer

In the neoadjuvant trial NEOSPHERE, the most common ADRs (≥50%) seen with Perjeta in combination with trastuzumab and docetaxel were alopecia and neutropenia. The most common NCI-CTCAE v.3 Grade 3-4 ADR (≥10%) was neutropenia.

In the neoadjuvant trial TRYPHAENA, when Perjeta was administered in combination with trastuzumab and FEC (5-fluorouracil, epirubicin, cyclophosphamide) for 3 cycles followed by 3 cycles of Perjeta, trastuzumab and docetaxel, the most common ADRs (≥50%) were neutropenia, diarrhoea and nausea. The most common NCI-CTCAE v.3 Grade 3-4 ADRs (≥10%) were neutropenia, febrile neutropenia and leucopenia. When Perjeta was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC (5-fluorouracil, epirubicin, cyclophosphamide), the most common ADRs (≥50%) were diarrhoea, nausea and alopecia. The most common NCI-CTCAE v.3 Grade 3-4 ADRs (≥10%) were neutropenia and leucopenia. Similarly, when Perjeta was administered in combination with TCH (docetaxel, carboplatin and trastuzumab) for 6 cycles, the most common ADRs (≥50%) were diarrhoea and alopecia. The most common NCI-CTCAE v.3 Grade 3-4 ADRs (≥10%) were neutropenia, febrile neutropenia, anaemia, leucopenia and diarrhoea. The safety of Perjeta administered for more than 6 cycles in the neoadjuvant setting has not been established.

Tabulated list of adverse reactions

Table 1 summarizes the ADRs from the pivotal clinical trial CLEOPATRA, in which Perjeta was given in combination with docetaxel and trastuzumab  to patients with metastatic breast cancer, and from the neoadjuvant trials NEOSPHERE and TRYPHAENA, in which Perjeta was given in combination with trastuzumab and chemotherapy to patients with early breast cancer.. As Perjeta is used with trastuzumab and chemotherapydocetaxel, it is difficult to ascertain the causal relationship of an adverse event to a particular medicinal product. The safety of Perjeta in phase I and phase II studies was generally consistent with that observed in the CLEOPATRA trial, though the incidence and most common ADRs varied depending on whether Perjeta was administered as monotherapy or with concomitant anti-neoplastic agents.

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, adverse reactions are presented in the order of decreasing seriousness.

Table 1         Summary of ADRs in patients treated with Perjeta in the metastatic and neoadjuvant setting^  from the pivotal clinical trial CLEOPATRA

^{^}  Table 1 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)

* Including adverse reactions with a fatal outcome.  

** For the overall treatment period across the 3 studies.

† Except for febrile neutropenia, neutropenia, leucopenia, lacrimation increased, interstitial lung disease, paronychia, and alopecia, all events in this table were also reported in at least 1% of patients participating in Perjeta monotherapy trials, although not necessarily considered causally related to Perjeta by the investigator. Very common events (reported in ≥ 10% of Perjeta monotherapy-treated patients) are marked in the Table with a †.

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

°° Infusion reaction/cytokine release syndrome includes a range of different terms within a time window, see “Description of selected adverse reactions” below.

ADRs reported in patients receiving Perjeta and trastuzumab after discontinuation of docetaxel

In the pivotal trial CLEOPATRA, ADRs were reported less frequently after discontinuation of docetaxel treatment. After discontinuation of docetaxel, ADRs in the Perjeta and trastuzumab treated group occurred in < 10% of patients with the exception of diarrhoea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), nasopharyngitis (17.0%), asthenia (13.4%), pruritus (13.7%), arthralgia (11.4%), nausea (12.7%), pain in extremity (13.4%), back pain (12.1%) and cough (12.1%).

Description of selected adverse reactions

Left ventricular dysfunction

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 (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. 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.

Infusion reactions

An infusion reaction was defined in the pivotal trial CLEOPATRA in metastatic breast cancer 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 the NEOSPHERE and TRYPHAENA trials in the neoadjuvant setting, Perjeta was administered on the same day as the other study treatment drugs in all cycles. Infusion reactions were consistent with those observed in CLEOPATRA at the cycles when Perjeta was given on the same day as trastuzumab and docetaxel, with a majority of reactions being mild or moderate.

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 NEOSPHERE and TRYPHAENA trials in the neoadjuvant setting, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In NEOSPHERE, two patients in the Perjeta and docetaxel-treated group experienced anaphylaxis. In TRYPHAENA, the overall frequency of hypersensitivity/anaphylaxis was highest in the Perjeta and TCH treated group (13.2%), of which 2.6% were NCI-CTCAE v.3 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. 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 amongfor 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.

Diarrhoea

In the pivotal clinical trial CLEOPATRA in metastatic breast cancer, diarrhoea occurred in 68.4% of Perjeta-treated patients and 48.7% of placebo-treated patients. Most events were mild to -moderate in severity and occurred in the first few cycles of treatment. The incidence of NCI-CTCAE Grade 3-4 diarrhoea was 9.3% in Perjeta-treated patients vs 5.1% in placebo-treated patients. The median duration of the longest episode was 18 days in Perjeta-treated patients and 8 days in placebo-treated patients. Diarrhoeal events responded well to proactive management with anti-diarrhoeal agents.

In the NEOSPHERE trial, diarrhoea occurred in 45.8% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel compared with 33.6% of patients treated with trastuzumab and docetaxel. In the TRYPHAENA trial, diarrhoea occurred in 72.3% of patients treated with neoadjuvant Perjeta+TCH and 61.4% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel following FEC. In both studies most events were mild to moderate in severity.

Rash

In the pivotal trial CLEOPATRA in metastatic breast cancer, rRash occurred in 51.7% of Perjeta-treated patients, compared with 38.9% of placebo-treated patients. Most events were Grade 1 or 2 in severity, occurred in the first two cycles, and responded to standard therapies, such as topical or oral treatment for acne.

In the NEOSPHERE trial, rash occurred in 40.2% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel compared with 29.0% of patients treated with trastuzumab and docetaxel. In the TRYPHAENA trial, rash occurred in 36.8% of patients treated with neoadjuvant Perjeta + TCH and 20.0% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel following FEC. The incidence of rash was higher in patients who received six cycles of Perjeta compared with patients who received three cycles of Perjeta, independent of the chemotherapy given.

Laboratory abnormalities

In the pivotal trial CLEOPATRA in metastatic breast cancer, theThe incidence of NCI-CTCAE v.(version 3) Grade 3-4 neutropenia was balanced in the two treatment groups (86.3% of Perjeta-treated patients and 86.6% of placebo-treated patients, including 60.7% and 64.8% Grade 4 neutropenia, respectively).

In the NEOSPHERE trial, the incidence of NCI-CTCAE v.3 Grade 3-4 neutropenia was 74.5% in patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel compared with 84.5% in patients treated with trastuzumab and docetaxel, including 50.9% and 60.2% Grade 4 neutropenia, respectively. In the TRYPHAENA trial, the incidence of NCI-CTCAE v.3 Grade 3-4 neutropenia was 85.3% in patients treated with neoadjuvantPerjeta + TCH and 77.0% in patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel following FEC, including 66.7% and 59.5% Grade 4 neutropenia, respectively.

[…]

5.1          Pharmacodynamic properties

[…]

Perjeta in combination with trastuzumab and docetaxel

CLEOPATRA (WO20698) is a multicentre, randomised, double-blind, placebo-controlled phase III clinical trial conducted in 808 patients with HER2-positive metastatic or locally recurrent unresectable breast cancer. Patients with clinically important cardiac risk factors were not included (see section 4.4). Due to the exclusion of patients with brain metastases no data are available on Perjeta activity on brain metastases. There is very limited data available in patients with unresectable locally recurrent disease. Patients were randomized 1:1 to receive placebo + trastuzumab + docetaxel or Perjeta + trastuzumab + docetaxel.

[…]

Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as estrogenoestrogen receptor (ER) -positive and/or progesterone receptor (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 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.

[…]

Neoadjuvant Treatment of Breast Cancer

In the neoadjuvant setting, locally advanced and inflammatory breast cancers are considered as high-risk irrespective of hormone receptor status. In early stage breast cancer, tumor size, grade, hormone receptor status and lymph node metastases should be taken into account in the risk assessment.

The indication in the neoadjuvant treatment of breast cancer is based on demonstration of an improvement in pathological complete response rate, and trends to improvement in disease-free survival that nevertheless do not establish or precisely measure a benefit with regard to long-term outcomes, such as overall survival or disease-free survival.

NEOSPHERE (WO20697)

NEOSPHERE WO20697 - randomised comparative trial in the neoadjuvant setting

NeoSphere (WO20697) is a phase II, multicentre, multinational randomized controlled trial study with Perjeta and was conducted in 417 adult female patients with newly diagnosed, early, inflammatory or, locally advanced HER2-positive breast cancer (T2-4d; primary tumour > 2cm in diameter) who had not 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 therapy. Prior to surgery, patients were less than 65 years old.

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

·      Trastuzumab plus docetaxel

·      Perjeta plus trastuzumab and docetaxel

·      Perjeta plus trastuzumab

·      Perjeta plus docetaxel.

Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER or PgR positivity. 

Perjeta was given intravenously at an initial dose of 840 mg, followed by 420 mg every three weeks. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every three weeks. Docetaxel was given intravenously at an initial dose of 75 mg/ m² followed by 75 mg/ m² or 100 mg/ m² (if tolerated) every 3 weeks. Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m²), epirubicin (90 mg/m²), cyclophosphamide (600 mg/m²) (FEC) given intravenously every three weeks, and trastuzumab administered intravenously every three weeks to complete one year of therapy. Patients who only received Perjeta plus trastuzumab prior to surgery subsequently received both FEC and docetaxel post surgery.

four treatment groups, as described in Table 3. The primary endpoint of the study was pathological complete response (pCR) rate in the breast (ypT0/is).  Secondary efficacy endpoints were clinical response rate, breast conserving surgery rate (T2-3 tumours only), disease-free survival (DFS), and PFS. Additional exploratory pCR rates included nodal status (ypT0/isN0 and ypT0N0).

Demographics were well balanced (median age was 49-50 years, the majority were caucasian (71%)) and all patients were female. Overall 7% of patients had inflammatory breast cancer, 32% had locally advanced breast cancer and 61% had operable breast cancer.  Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as ER positive and/or PgR positive).

following neoadjuvant therapy. The efficacy results are presented in Table 3. A statistically significant  improvement in pCR rate (ypT0/is) was observed in patients receiving Perjeta plus trastuzumab and docetaxel compared to patients receiving trastuzumab and docetaxel (45.8% vs 29.0%, p value = 0.0141). A consistent pattern of results was observed regardless of pCR definition . The difference in pCR rate is considered likely to translate into a clinically meaningful difference in long term outcomes and is supported by positive trends in PFS (HR 0.69, 95% CI 0.34, 1.40) and DFS (HR 0.60, 95% CI 0.28, 1.27).

The pCR rates as well as the magnitude of benefit with Perjeta (Perjeta plus trastuzumab and docetaxel compared to patients receiving trastuzumab and docetaxel) were lower in the subgroup of patients with hormone receptor-positive tumours (difference of 6% in pCR in the breast) than in patients with hormone receptor-negative tumours (difference of 26.4% in pCR in the breast).

pCR rates were similar in patients with operable versus locally advanced disease. There were too few patients with inflammatory breast cancer to draw any firm conclusions but the pCR rate was higher in patients who received Perjeta plus trastuzumab and docetaxel.

TRYPHAENA (BO22280)

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

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

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

·      6 cycles of TCH in combination with Perjeta.

Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and /or PgR positivity.

Perjeta was given intravenously at an initial dose of 840 mg, followed by 420 mg every three weeks.  Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every three weeks.  FEC (5-fluorouracil [500 mg/m²], epirubicin [100 mg/m2], cyclophosphamide [600 mg/m2]) were given intravenously every three weeks for 3 cycles.  Docetaxel was given as an initial dose of 75 mg/m² IV infusion every three weeks with the option to escalate to 100 mg/m² at the investigator’s discretion if the initial dose was well tolerated.  However, in the group treated with Perjeta in combination with TCH, docetaxel was given intravenously at 75 mg/m²  (no escalation was permitted) and carboplatin (AUC 6) was given intravenously every three weeks. Following surgery all patients received trastuzumab to complete one year of therapy.

The primary endpoint of this study was cardiac safety during the neoadjuvant treatment period of the study.  Secondary efficacy endpoints were pCR rate in the breast (ypT0/is), DFS, PFS and OS.

Demographics were well balanced between arms (median age was 49-50 years, the majority were Caucasian [77%]) and all patients were female. Overall 6% of patients had inflammatory breast cancer, 25% had locally advanced breast cancer and 69% had operable breast cancer. Approximately half the patients in each treatment group had ER-positive and/or PgR-positive disease.

Compared with published data for similar regimens without pertuzumab, high pCR rates were observed in all 3 treatment arms (see Table 3). 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.

Table 3         NEOSPHERE (Study WO20697) and TRYPHAENA (BO22280): Overview: Summary of efficacyPrimary Efficacy – pCR Rate (Intent to Treat Population)

FEC: 5-fluorouracil, epirubicin, cyclophosphamide; TCH: docetaxel, carboplatin and trastuzumab, CMH: Cochran–Mantel–Haenszel

1. 95% CI for one sample binomial using Pearson-Clopper method.

2. Treatment Perjeta+Trastuzumab+Docetaxel and Perjeta+Trastuzumab are compared to Trastuzumab+ Docetaxel while Perjeta+Docetaxel  is compared to Perjeta+Trastuzumab+Docetaxel.

3. Approximate 95% CI for difference of two response rates using Hauck-Anderson method.

4. p-value from Cochran-Mantel-Haenszel  test, with Simes multiplicity adjustment.

5. Clinical response represents patients with a best overall response of CR or PR during the neoadjuvant period (in the primary breast lesion).

1 Perjeta and/or trastuzumab were given at standard doses in a 3-weekly regimen for 4 cycles. Docetaxel 75 mg/m² was escalated, if tolerated, to 100 mg/m² intravenous every 3 weeks for 4 cycles.

2  pCR defined as elimination of all invasive disease from the breast.

3  95% CI for one sample binomial using the Pearson-Clopper method.

4 Treatment Group B and C are compared to Group A while Group D is compared to Group B.

5 Approximate 95% CI for difference of two response rates using Hauck-Anderson method.

6  p-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.

Immunogenicity

Patients in the pivotal trial CLEOPATRA were tested at multiple time-points for anti-therapeutic antibodies (ATA) to Perjeta. Approximately 2.8% (11/386 patients) of Perjeta-treated patients and 6.2% (23/372 patients) of placebo-treated patients tested positive for ATAs. Of these 34 patients, none experienced severe (NCI-CTCAE Grade 4) infusion or hypersensitivity reactions (anaphylaxis) that were clearly related to ATA. However, Grade 3 hypersensitivity reactions associated with detectable ATAs occurred in 2 of 366 Perjeta-treated patients (0.5%) in phase I and II studies. There are currently insufficient data to evaluate the effects of ATA on the efficacy of Perjeta in combination with trastuzumab and docetaxel.

Paediatric population

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

5.2          Pharmacokinetic properties

[…]

The PK results of pertuzumab in the NEOSPHERE study are consistent with the predictions from the previous population PK model.

6.6          Special precautions for disposal and other handling

[…]

The vial must not be shaken. 14 ml  of Perjeta concentrate should be withdrawn from the vial and diluted into a 250 ml PVC or non-PVC polyolefin infusion bag of sodium chloride 9 mg/ml (0.9%) solution for infusion. After dilution, one ml of solution should contain approximately 3.36 3.02 mg of pertuzumab (840 mg/250278 ml) for the initial dose where two vials are required and approximately 1.68 1.59 mg of pertuzumab (420 mg/250264  ml) for the maintenance dose where one vial is required.

The bag should be gently inverted to mix the solution in order to avoid foaming.

[…]

10.          DATE OF REVISION OF THE TEXT

28 July 2015

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

4.2       Posology and method of administration

Hypersensitivity reactions/anaphylaxis

The infusion should be discontinued immediately if the patient experiences a NCI-CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.4).

4.4       Special warnings and precautions for use

In order to improve traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded (or stated) in the patient file.

Left ventricular dysfunction (including congestive heart failure)

Decreases in LVEF have been reported with medicinal products that block HER2 activity, including Perjeta. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines. In the pivotal trial CLEOPATRA, Perjeta in combination with trastuzumab and docetaxel was not associated with a greater incidence of symptomatic left ventricular systolic dysfunction (LVSD) or LVEF declines compared with placebo and trastuzumab and docetaxel (see section 4.8).

Perjeta has not been studied in patients with: a pre-treatment LVEF value of ≤ 50%; a prior history of congestive heart failure (CHF); LVEF declines to < 50% during prior trastuzumab adjuvant therapy; or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m² of doxorubicin or its equivalent.

Assess LVEF prior to initiation of Perjeta and every three cycles during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40% or 40%-45% associated with ≥ 10% points below the pretreatment value, Perjeta and trastuzumab should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If the LVEF has not improved, or has declined further, discontinuation of Perjeta and trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks (see section 4.2).

Infusion reactions, hypersensitivity reactions/anaphylaxis

Perjeta has been associated with infusion and hypersensitivity reactions (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 following the administration of Perjeta. If a significantn 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, has been observed in clinical trials with Perjeta (see section 4.8). Medications 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). Perjeta is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients (see section 4.3).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).

4.8       Undesirable effects

Summary of the safety profile

The safety of Perjeta has been evaluated in more than 1,400 patients either in the pivotal trial CLEOPATRA or in phase I and phase II trials conducted in patients with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic agents.

In the pivotal clinical trial CLEOPATRA, 408407 patients received at least one dose of Perjeta in combination with trastuzumab and docetaxel. The most common adverse drug reactions (ADRs) (≥> 50%) were diarrhoea, alopecia and neutropenia. The most common NCI-CTCAE (version 3) Grade 3-4 ADRs (> 10%) were neutropenia, febrile neutropenia and leucopenia, and the most common serious adverse events were febrile neutropenia, neutropenia and diarrhoea. Treatment-related deaths occurred in 1.2% of patients in the Perjeta-treated group and 1.5% of patients in the placebo-treated group and were mainly due to febrile neutropenia and/or infection. After 1 year of additional follow-up, left ventricular dysfunction occurred at a frequency of <10% in the pivotal clinical trial CLEOPATRA (5.4% in the Perjeta-treated group and 8.6% in the placebo-treated group, including symptomatic left ventricular systolic dysfunction in 1.2% in the Perjeta-treated group and 3.3% of patients in the placebo-treated group).

[...]

* Including adverse reactions with a fatal outcome. 

† Except for febrile neutropenia, neutropenia, leucopenia, lacrimation increased, interstitial lung disease, paronychia, and alopecia, all events in this table were also reported in at least 1% of patients participating in Perjeta monotherapy trials, although not necessarily considered causally related to Perjeta by the investigator. Very common events (reported in ≥ 10% of Perjeta monotherapy-treated patients) are marked in the Table with a †.

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

°° Infusion  related reaction/cytokine release syndrome includes a range of different terms within a time window, see “Description of selected adverse reactions” below.

ADRs reported in patients receiving Perjeta and trastuzumab after discontinuation of docetaxel

In the pivotal trial CLEOPATRA, ADRs were reported less frequently after discontinuation of docetaxel treatment. After discontinuation of docetaxel, all ADRs in the Perjeta and trastuzumab treated group occurred in < 10% of patients with the exception of diarrhoea (19.128.1%), upper respiratory tract infection (18.312.8%), rash (18.311.7%), headache (17.011.4%), and  fatigue (13.411.1%), nasopharyngitis (17.0%), asthenia (13.4%), pruritus (13.7%), arthralgia (11.4%), nausea (12.7%), pain in extremity (13.4%), back pain (12.1%) and cough (12.1%).

Description of selected adverse reactions

Left ventricular dysfunction

In the pivotal trial CLEOPATRA, 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).

Infusion reactions, hypersensitivity reactions/anaphylaxis

An infusion reaction was defined in the pivotal trial CLEOPATRA as any event (regardless of causality) described 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 13.213.0% 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, hypersensitivity, myalgia and vomiting (see section 4.4).

Hypersensitivity reactions/anaphylaxis

In the pivotal trial CLEOPATRA, the overall frequency of investigator reported hypersensitivity/anaphylaxis events (not including acute infusion reactions/cytokine release syndrome) during the entire treatment period was 9.39.1% in the placebo-treated group and 11.310.8% 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.

Febrile neutropenia

In the pivotal trial CLEOPATRA, the majority of patients in both treatment groups experienced at least one leucopenic event (63.062.4% of patients in the Perjeta-treated group and 58.358.2% of patients in the placebo-treated group), of which the majority were neutropenic events. Febrile neutropenia occurred in 13.713.8% 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 for 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 (25.826%) compared with the placebo-treated group (11.312%).

Diarrhoea

In the pivotal clinical trial CLEOPATRA, diarrhoea occurred in 68.466.8% of Perjeta-treated patients and 46.38.7% of placebo-treated patients. Most events were mild-moderate in severity and occurred in the first few cycles of treatment. The incidence of NCI-CTCAE Grade 3-4 diarrhoea was 7.99.3% in Perjeta-treated patients vs 5.05.1% in placebo-treated patients. The median duration of the longest episode was 1817 days in Perjeta-treated patients and 8 days in placebo-treated patients. Diarrhoeal events responded well to proactive management with anti-diarrhoeal agents.

Rash

Rash occurred in 45.251.7% of Perjeta-treated patients, compared with 38.936.0% 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.

Laboratory abnormalities

The incidence of NCI-CTCAE (version 3) Grade 3-4 neutropenia was balanced in the two treatment groups (86.385.9% of Perjeta-treated patients and 86.6% of placebo-treated patients, including 60.761.0% and 64.864.3% Grade 4 neutropenia, respectively).

[...]

5.1       Pharmacodynamic properties

[...]
 

The primary endpoint of the study was progression-free survival (PFS) as assessed by an independent review facility (IRF) and defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumour assessment. Secondary efficacy endpoints were overall survival (OS), PFS (investigator-assessed), objective response rate (ORR), duration of response, and time to symptom progression according to the FACT B Quality of Life questionnaire.

* p-value met the O’Brien Fleming stopping boundary of the Lan DeMets alpha spending function for the interim analysis of overall survival (p ≤ 0.0138). The result was therefore statistically significant.* Primary progression-free survival analysis, cutoff date 13^th May 2011.

** Final analysis of overall survival, cutoff date 11^th 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.

At an interim analysis of OS analysis performed one year after the primary analysis of efficacy,demonstrated a 267 patients had died with more deaths occurring in the placebo-treated group compared with the Perjeta-treated group. A statistically significant overall survival benefit in favour of the Perjeta-treated group was demonstrated(HR 0.66, p = 0.0008 log-rank test). The median time to death was 37.6 months in the placebo-treated group but had not yet been reached in the Perjeta-treated group.

The final analysis of OS was performed when 389 patients had died (221 in the placebo-treated group and 168 in the Perjeta-treated group). The statistically significant OS benefit in favour of the Perjeta-treated group, previously observed at an interim analysis of OS (performed one year after the primary analysis), was maintained (HR 0.68, p = 0.0002 log-rank test). The median time to death was 40.8 months in the placebo-treated group and 56.5 months in the Perjeta-treated group (see Table 2, Figure 2).

10.       DATE OF REVISION OF THE TEXT

26 March 2015

Underlined text has been added, text with strike through deleted:

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 3.36 mg of pertuzumab for the initial dose and approximately 1.68 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.

4.2          Posology and method of administration

Perjeta is subject to restricted medical prescription and therapy 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 service isfacilities are immediately available.

[…]

4.6          Fertility, pregnancy and lactation

Contraception in males and females

Women of childbearing potential and male patients with female partners of childbearing potential, must use effective contraception while receiving Perjeta and for 6 months following the last dose of Perjeta. Women of childbearing potential should use effective contraception while receiving Perjeta and for 6 months following the last dose of Perjeta.

[…]

4.8          Undesirable effects

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 (see details below).

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

via the national reporting system listed in Appendix V.

6.6          Special precautions for disposal and other handling

Perjeta does not contain any antimicrobial preservative. Therefore, care must be taken to ensure the sterility of the prepared solution for infusion and should be prepared by a healthcare professional.

Perjeta is for single use only and is administered intravenously by infusion.

The vial must not be shaken. 14 ml All the of Perjeta concentrate should be withdrawn from the vial should be mixed and diluted into a 250 ml PVC or non-PVC polyolefin infusion bag of sodium chloride 9 mg/ml (0.9%) solution for infusion. After dilution, one ml of solution should contain approximately 3.36 mg of pertuzumab (840 mg/250 ml) for the initial dose where two vials are required and approximately 1.68 mg of pertuzumab (420 mg/250 ml) for the maintenance dose where one vial is required.

The bag should be gently inverted to mix the solution in order to avoid foaming.

Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. If particulates or discoloration are observed, the solution should not be used. Once the infusion is prepared it should be administered immediately (see section 6.3).

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

6.3       Shelf life

Unopened vial

3 2 years.

10.       DATE OF REVISION OF THE TEXT

17^th june 2013