Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

Left ventricular dysfunction (including congestive heart failure)

Decreases in LVEF have been reported with medicinal products that block HER2 activity, including Perjeta.
The incidence of symptomatic left ventricular systolic dysfunction (LVD) [congestive heart failure] was higher in patients treated with Perjeta in combination with trastuzumab and chemotherapy compared with trastuzumab and chemotherapy . Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines. The majority of cases of symptomatic heart failure reported in the adjuvant setting were in patients who received anthracycline-based chemotherapy (see section 4.8).

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

Assess LVEF prior to initiation of Perjeta and at regular intervals during treatment with Perjeta (e.g. once during neoadjuvant treatment and every 12 weeks in the adjuvant or metastatic setting) to ensure that LVEF is within normal limits. If the LVEF has declined as indicated in section 4.2 and has not improved, or has declined further at the subsequent assessment, discontinuation of Perjeta and trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks.

Cardiac risk should be carefully considered and balanced against the medical need of the individual patient before use of Perjeta with an anthracycline. Based on the pharmacological actions of HER2-targeted agents and anthracyclines, the risk of cardiac toxicity might be expected to be higher with concomitant use of Perjeta and anthracyclines than with sequential use.

Sequential use of Perjeta (in combination with trastuzumab and a taxane) has been evaluated following the epirubicin or doxorubicin component of many anthracycline-based regimens in the APHINITY and BERENICE studies. However, only limited safety data are available on concurrent use of Perjeta and an anthracycline. In the TRYPHAENA study, Perjeta was given concurrently with epirubicin, as part of the FEC (5-fluorouracil, epirubicin, cyclophosphamide) regimen (see sections 4.8 and 5.1). Only chemotherapy- naive patients were treated and they received low cumulative doses of epirubicin (up to 300 mg/m2). In this study, cardiac safety was similar to that observed in patients given the same regimen but with Perjeta administered sequentially (following FEC chemotherapy).

Infusion reactions

Perjeta has been associated with infusion reactions, including events with a fatal outcome (see section 4.8).
Close observation of the patient during and for 60 minutes after the first infusion and during and for 30-60 minutes after subsequent infusions of Perjeta is recommended. If a significant infusion reaction occurs, the infusion should be slowed down or interrupted and appropriate medical therapies should be administered.
Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms.
Permanent discontinuation should be considered in patients with severe infusion reactions. This clinical assessment should be based on the severity of the preceding reaction and response to administered treatment for the adverse reaction (see section 4.2).

Hypersensitivity reactions/anaphylaxis

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis and events with a fatal outcome, has been observed with Perjeta (see section 4.8). Medicinal products to treat such reactions, as well as emergency equipment, should be available for immediate use.
Perjeta must be permanently discontinued in case of NCI-CTCAE Grade 4 hypersensitivity reactions (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.2).

Febrile neutropenia

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

Diarrhoea

Perjeta may elicit severe diarrhoea. Diarrhoea is most frequent during concurrent administration with taxane therapy. Elderly patients (> 65 years) have a higher risk of diarrhoea compared with younger patients (< 65 years). Treat diarrhoea according to standard practice and guidelines. Early intervention with loperamide, fluids and electrolyte replacement should be considered, particularly in elderly patients, and in case of severe or prolonged diarrhoea. Interruption of treatment with pertuzumab should be considered if no improvement in the patient’s condition is achieved. When the diarrhoea is under control treatment with pertuzumab may be reinstated.



Effects on Driving

4.7     Effects on ability to drive and use machines

On the basis of reported adverse reactions, Perjeta has a minor influence on the ability to drive or use machines. Dizziness may occur during treatment with Perjeta (see section 4.8). Patients experiencing infusion reactions should be advised not to drive and use machines until symptoms abate.