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 the 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 pertuzumab and trastuzumab. The incidence of symptomatic left ventricular systolic dysfunction (LVD [congestive heart failure]) was higher in patients treated with pertuzumab in combination with trastuzumab and chemotherapy compared to trastuzumab and chemotherapy. In the adjuvant setting, the majority of cases of symptomatic heart failure reported were in patients who received anthracycline-based chemotherapy (see section 4.8). Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines based on studies with intravenous pertuzumab in combination with trastuzumab and chemotherapy.

Patients with history of serious cardiac illness or medical conditions, history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias were excluded from the (neo-)adjuvant EBC pivotal trial FEDERICA with Phesgo.
Phesgo has not been studied in patients with: a pretreatment LVEF value of < 55 % (EBC) or < 50 % (MBC); a prior history of congestive heart failure (CHF); 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. In addition, pertuzumab in combination with trastuzumab and chemotherapy has not been studied in patients with decreases in LVEF < 50 % during prior trastuzumab adjuvant therapy.

Assess LVEF prior to initiation of Phesgo and at regular intervals during treatment (e.g. once during neoadjuvant treatment and every 12 weeks in the adjuvant and 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 Phesgo 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 Phesgo 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 Phesgo and anthracyclines than with sequential use.

Sequential use of Phesgo (in combination with a taxane) has been evaluated following the doxorubicin component of two anthracycline-based regimens in the FEDERICA study while sequential use of intravenous pertuzumab (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. Only limited safety data are available on concurrent use of intravenous pertuzumab in combination with trastuzumab and an anthracycline. In the TRYPHAENA study, intravenous pertuzumab in combination with trastuzumab 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 pertuzumab administered sequentially (following FEC chemotherapy).

Injection-related reactions/infusion-related reactions (IRRs)

Phesgo has been associated with injection-related reactions (see section 4.8). Injection-related reactions were defined as any systemic reaction with symptoms such as fever, chills, headache, likely due to a release of cytokines occurring within 24 hour of administration of Phesgo. Close observation of the patient during and for 30 minutes after administration of the loading dose and during and for 15 minutes following the administration of the maintenance dose of Phesgo is recommended. If a significant injection-related reaction occurs, the injection should be slowed down or paused 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 injection-related 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). Although fatal outcomes resulting from injection-related reactions have not been observed with Phesgo, caution should be exercised, as fatal infusion related-reactions have been associated with intravenous pertuzumab in combination with intravenous trastuzumab and chemotherapy.

Hypersensitivity reactions/anaphylaxis

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity reactions, including anaphylaxis and events with fatal outcomes, have been observed with pertuzumab in combination with trastuzumab and chemotherapy (see section 4.8). The majority of anaphylactic reactions occurred within the first 6-8 cycles of treatment when pertuzumab and trastuzumab were given in combination with chemotherapy. Medicinal products to treat such reactions, as well as emergency equipment, should be available for immediate use. Phesgo must be permanently discontinued in case of NCI-CTCAE Grade 4 hypersensitivity reactions (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.2). Phesgo is contraindicated in patients with known hypersensitivity to pertuzumab, trastuzumab or to any of its excipients (see section 4.3).

Febrile neutropenia

Patients treated with Phesgo in combination with a taxane are at increased risk of febrile neutropenia.
Patients treated with intravenous pertuzumab in combination with 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 pertuzumab-treated and placebo- treated patients. The higher incidence of febrile neutropenia in pertuzumab-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

Phesgo 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 Phesgo should be considered if no improvement in the patient’s condition is achieved. When the diarrhoea is under control treatment with Phesgo may be reinstated.

Pulmonary events

Severe pulmonary events have been reported with the use of trastuzumab in the post-marketing setting. These events have occasionally been fatal. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency also have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Phesgo. Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Phesgo has minor influence on the ability to drive and use machines (see section 4.8). Patients experiencing injection-related reactions or dizziness (see section 4.4) should be advised not to drive and use machines until symptoms abate.