Perjeta 420 mg concentrate for solution for infusion

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.

Concentrate for solution for infusion.

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

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.

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 facilities are immediately available.

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.

Posology

The recommended initial loading dose of Perjeta 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.

When administered with Perjeta the recommended initial loading dose of trastuzumab is 8 mg/kg body weight administered as an intravenous infusion followed every 3 weeks thereafter by a maintenance dose of 6 mg/kg body weight.

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 medicinal products should be administered sequentially. 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).

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

Delayed or missed doses

If the time between two sequential infusions is less than 6 weeks, the 420 mg dose of Perjeta should be administered as soon as possible without regard to the next planned dose.

If the time between two sequential infusions is 6 weeks or more, the initial loading dose of 840 mg Perjeta should be re-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.

Dose modification

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 dose modifications, see docetaxel 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.

Left ventricular dysfunction

Perjeta and trastuzumab should be withheld for at least 3 weeks for any of the following:

- signs and symptoms suggestive of congestive heart failure (Perjeta should be discontinued if symptomatic heart failure is confirmed)

- a drop in left ventricular ejection fraction (LVEF) to less than 40%

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

Perjeta and trastuzumab may be resumed if the LVEF has recovered to > 45% or 40-45% associated with < 10% points below pretreatment value.

If after a repeat assessment within approximately 3 weeks, 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 4.4).

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. 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).

Elderly patients

Limited data are available on the safety and efficacy of pertuzumab in patients ≥ 65 years of age. No significant differences in safety and efficacy of pertuzumab 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.

Patients with renal impairment

Dose adjustments of Perjeta 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).

Patients with 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 metastatic 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 section 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).

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

In order to improve traceability of biological medicinal products, the tradename 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 is recommended following the administration of Perjeta. If an infusion reaction occurs, the infusion should be slowed down or interrupted and appropriate medical therapies should be administered. Patients should be eva luated and carefully monitored until complete resolution of signs and symptoms. 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). As nadir neutrophil counts were similar in Perjeta-treated and placebo-treated patients, the higher incidence of febrile neutropenia in Perjeta-treated patients may be associated with the higher incidence of mucositis and diarrhoea in these patients. Symptomatic treatment for mucositis and diarrhoea should be considered. In the pivotal trial, CLEOPATRA, no events of febrile neutropenia were reported after cessation of docetaxel.

No pharmacokinetic (PK) interactions were observed between Perjeta and trastuzumab, or between Perjeta and docetaxel in a sub-study of 37 patients in the randomised, pivotal trial CLEOPATRA. In addition, in the population PK analysis, no evidence of a drug-drug interaction has been shown between Perjeta and trastuzumab and between Perjeta and docetaxel.

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

Contraception

Women of childbearing potential should use effective contraception while receiving Perjeta and for 6 months following the last dose of Perjeta.

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 eva luate the effect of pertuzumab. Only very limited data are available from repeat-dose toxicity studies with respect to the risk for adverse effects on the male reproductive system. No adverse effects were observed in sexually mature female cynomolgus monkeys exposed to pertuzumab.

On the basis of reported adverse reactions, Perjeta is not expected to influence the ability to drive or use machines. Patients experiencing infusion reactions should be advised not to drive and use machines until symptoms abate.

Summary of the safety profile

The safety of Perjeta has been eva luated in more than 1,400 patients either in the pivotal trial CLEOPATRA or in phase I and 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, 407 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).

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. As Perjeta is used with trastuzumab and docetaxel, 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 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 from the pivotal clinical trial CLEOPATRA

* 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 (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%) and fatigue (11.1%).

Description of selected adverse reactions

Infusion reactions, hypersensitivity reactions/anaphylaxis

An infusion reaction was defined in the pivotal trial as any event (regardless of causality) described 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 13.0% 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.

In the pivotal trial CLEOPATRA, the overall frequency of hypersensitivity/anaphylaxis events (not including acute infusion reactions/cytokine release syndrome) during the entire treatment period was 9.1% in the placebo-treated group and 10.8% in the Perjeta-treated group, of which 2.5% and 2% 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 (62.4% of patients in the Perjeta-treated group and 58.2% of patients in the placebo-treated group), of which the majority were neutropenic events. Febrile neutropenia occurred in 13.8% 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 (26%) compared with the placebo-treated group (12%).

Diarrhoea

In the pivotal clinical trial CLEOPATRA, diarrhoea occurred in 66.8% of Perjeta-treated patients and 46.3% 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 7.9% in Perjeta-treated patients vs 5.0% in placebo-treated patients. The median duration of the longest episode was 17 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 45.2% of Perjeta-treated patients, compared with 36.0% 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 (85.9% of Perjeta-treated patients and 86.6% of placebo-treated patients, including 61.0% and 64.3% Grade 4 neutropenia, respectively).

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

The maximum tolerated dose of Perjeta has not been determined. In clinical trials, single doses higher than 25 mg/kg (1727 mg) have not been tested.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC13

Mechanism of action

Perjeta is a recombinant humanised monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2), and thereby, blocks ligand-dependent heterodimerisation of HER2 with other HER family members, including EGFR, HER3 and HER4. As a result, Perjeta inhibits ligand-initiated intracellular signalling through two major signal pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these signalling pathways can result in cell growth arrest and apoptosis, respectively. In addition, Perjeta mediates antibody-dependent cell-mediated cytotoxicity (ADCC).

While Perjeta alone inhibited the proliferation of human tumour cells, the combination of Perjeta and trastuzumab significantly augmented antitumour activity in HER2-overexpressing xenograft models.

Clinical efficacy and safety

The efficacy of Perjeta in HER2-positive breast cancer is supported by a randomised phase III comparative trial in metastatic breast cancer and two phase II studies (one single-arm trial in metastatic breast cancer and one randomised comparative trial in the neoadjuvant setting).

Metastatic breast cancer

Perjeta in combination with trastuzumab and docetaxel

CLEOPATRA 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.

Perjeta and trastuzumab were given at standard doses in a 3-weekly regimen. Patients were treated with Perjeta and trastuzumab until disease progression, withdrawal of consent or unmanageable toxicity. Docetaxel was given as an initial dose of 75 mg/m² as an intravenous infusion every three weeks for at least 6 cycles. The dose of docetaxel could be escalated to 100 mg/m² at the investigator's discretion if the initial dose was well tolerated.

The primary endpoint of the study was progression-free survival (PFS) as assessed by an independent review facility (IRF) and defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumour assessment.

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

The efficacy results from the CLEOPATRA study are summarised in Table 2. A statistically significant improvement in IRF-assessed PFS was demonstrated in the Perjeta-treated group compared with the placebo-treated group. The results for investigator-assessed PFS were similar to those observed for IRF-assessed PFS.

Table 2 Summary of efficacy from CLEOPATRA study

* 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.

** Patients with best overall response of confirmed CR or PR by RECIST.

† eva luated in patients with Best Overall Response of CR or PR.

^ Objective response rate and duration of response are based on IRF-assessed tumour assessments.

Consistent results were observed across pre-specified patient subgroups including the subgroups based on stratification factors of geographic region and prior adjuvant/neoadjuvant therapy or de novo metastatic breast cancer (see Figure 1). A post hoc exploratory analysis revealed that for patients who had received prior trastuzumab (n = 88), the hazard ratio for IRF-assessed PFS was 0.62 (95% CI 0.35, 1.07), compared with 0.60 (95% CI 0.43, 0.83) for patients who had received prior therapy which did not include trastuzumab (n = 288).

Figure 1 IRF-assessed PFS by patient subgroup

At an OS analysis performed one year after the primary analysis of efficacy, 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 (see Figure 2).

Figure 2 Kaplan-Meier Curve of Overall Survival

No statistically significant differences were found between the two treatment groups in Health Related Quality of Life as assessed by FACT-B TOI-PFB scores.

Additional supportive clinical trial information

BO17929 - single-arm trial in metastatic breast cancer

BO17929 was a phase II, non-randomised study in patients with metastatic breast cancer whose tumours had progressed during treatment with trastuzumab. Treatment with Perjeta and trastuzumab resulted in a response rate of 24.2%, with a further 25.8% of patients experiencing stabilisation of disease lasting at least 6 months, indicating that Perjeta is active following progression on trastuzumab.

WO20697 - randomised comparative trial in the neoadjuvant setting

NeoSphere (WO20697) is a phase II, multicentre, multinational study with Perjeta and was conducted in 417 patients with newly diagnosed, early, inflammatory, locally advanced HER2-positive breast cancer who had not received prior trastuzumab therapy. Prior to surgery, patients were randomised into one of four treatment groups, as described in Table 3. The primary endpoint of the study was pathological complete response (pCR) rate following neoadjuvant therapy. The efficacy results are presented in Table 3.

Table 3 Study WO20697: Summary of Primary Efficacy – pCR Rate (Intent to Treat Population)

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 eva luate 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).

A population pharmacokinetic analysis was performed with data from 481 patients across different clinical trials (phase I, II and III) with various types of advanced malignancies who had received Perjeta as a single agent or in combination at doses ranging from 2 to 25 mg/kg administered every 3 weeks as a 30-60 minutes intravenous infusion.

Absorption

Perjeta is administered as an intravenous infusion. There have been no studies performed with other routes of administration.

Distribution

Across all clinical studies, the volume of distribution of the central (Vc) and the peripheral (Vp) compartment in the typical patient, was 3.11 litres and 2.46 litres, respectively.

Biotransformation

The metabolism of Perjeta has not been directly studied. Antibodies are cleared principally by catabolism.

Elimination

The median clearance (CL) of Perjeta was 0.235 litres/day and the median half-life was 18 days.

Linearity/non-linearity

Perjeta displayed linear pharmacokinetics within the recommended dose range.

Elderly patients

Based on the population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of Perjeta between patients < 65 years (n=306) and patients ≥ 65 years (n=175).

Patients with renal impairment

No dedicated renal impairment trial for Perjeta has been conducted. Based on the results of the population pharmacokinetic analysis, Perjeta exposure in patients with mild (creatinine clearance [CLcr] 60 to 90 ml/min, N=200) and moderate renal impairment (CLcr 30 to 60 ml/min, N=71) was similar to that in patients with normal renal function (CLcr greater than 90 ml/min, N=200). No relationship between CLcr and Perjeta exposure was observed over the range of CLcr (27 to 244 ml/min).

Other special populations

The population PK analysis suggested no PK differences based on age, gender and ethnicity (Japanese versus non-Japanese). Baseline albumin and lean body weight were the most significant covariates influencing CL. CL decreased in patients with higher baseline albumin concentrations and increased in patients with greater lean body weight. However sensitivity analyses performed at the recommended dose and schedule of Perjeta showed that at the extreme values of these two covariates, there was no significant impact on the ability to achieve target steady-state concentrations identified in preclinical tumour xenograft models. Therefore, there is no need to adjust the dosage of Perjeta based on these covariates.

No specific fertility studies in animals have been performed to eva luate the effect of pertuzumab. No definitive conclusion on adverse effects can be drawn on the male reproductive organs in cynomolgus monkey repeated dose toxicity study.

Reproductive toxicology studies have been conducted in pregnant cynomolgus monkeys (Gestational Day (GD) 19 through to GD 50) at initial doses of 30 to 150 mg/kg followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on C_max. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-foetal death between GD25 to GD70. The incidences of embryo-foetal loss were 33, 50, and 85% for pregnant female monkeys treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on C_max). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. In addition, consistent with foetal growth restrictions, secondary to oligohydramnios, lung hypoplasia (1 of 6 in 30 mg/kg and 1 of 2 in100 mg/kg groups), ventricular septal defects (1 of 6 in 30 mg/kg group), thin ventricular wall (1 of 2 in 100 mg/kg group) and minor skeletal defects (external - 3 of 6 in 30 mg/kg group) were also noted. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.

In cynomolgus monkeys, weekly intravenous administration of pertuzumab at doses up to 150 mg/kg/dose was generally well tolerated. With doses of 15 mg/kg and higher, intermittent mild treatment-associated diarrhoea was noted. In a subset of monkeys, chronic dosing (7 to 26 weekly doses) resulted in episodes of severe secretory diarrhoea. The diarrhoea was managed (with the exception of euthanasia of one animal, 50 mg/kg/dose) with supportive care including intravenous fluid replacement therapy.

Acetic acid, glacial

L-Histidine

Sucrose

Polysorbate 20

Water for Injections

No incompatibilities between Perjeta and polyvinylchloride (PVC) or non-PVC polyolefin bags including polyethylene have been observed. Glucose (5%) solution should not be used to dilute Perjeta since it is chemically and physically unstable in such solutions.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial

2 years.

Diluted solution

Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Vial (Type I glass) with a stopper (butyl rubber) containing 14 ml of solution.

Pack of 1 vial.

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 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 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.

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

EU/1/13/813/001

Date of first authorisation: 4^th March 2013

13 Sep 2013

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