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

Pertuzumab is a humanised IgG1 monoclonal antibody produced in mammalian (Chinese hamster ovary) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

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

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)

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 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).

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 and other chemotherapy dose modifications, see relevant 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.

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.

Hypersensitivity reactions/anaphylaxis

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

Elderly patients

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

Method of administration

Perjeta is administered intravenously by infusion. It should not be administered as an intravenous push or bolus. For instructions on dilution of Perjeta prior to administration, see sections 6.2 and 6.6.

For the initial dose, the recommended infusion period is 60 minutes. If the first infusion is well tolerated, subsequent infusions may be administered over a period of 30 minutes to 60 minutes (see section 4.4).

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 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 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 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).

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 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). Cardiac safety data from the BERENICE study, in which patients were treated sequentially with either epirubicin or doxorubicin followed by Perjeta and trastuzumab, were consistent with previous data in the neoadjuvant setting (see section 4.8).

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.

Infusion reactions

Perjeta has been associated with infusion 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. If a significant 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. 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).

Febrile neutropenia

Patients treated with Perjeta, trastuzumab and docetaxel are at increased risk of febrile neutropenia compared with patients treated with placebo, trastuzumab and docetaxel, especially during the first 3 cycles of treatment (see section 4.8). In the CLEOPATRA trial in metastatic breast cancer, nadir neutrophil counts were similar in Perjeta-treated and placebo-treated patients. The higher incidence of febrile neutropenia in Perjeta-treated patients was associated with the higher incidence of mucositis and diarrhoea in these patients. Symptomatic treatment for mucositis and diarrhoea should be considered. No events of febrile neutropenia were reported after cessation of docetaxel.

Diarrhoea

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.