4.1. Therapeutic indications

Early breast cancer (EBC)

Phesgo is indicated for use in combination with chemotherapy in:

• 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)

• the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence (see section 5.1)

Metastatic breast cancer (MBC)

Phesgo is indicated for use in combination with 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.

4.2. Posology and method of administration

Phesgo should only be initiated under the supervision of a physician experienced in the administration of anti-cancer agents. Phesgo should be administered by a healthcare professional prepared to manage anaphylaxis and in an environment where full resuscitation facilities are immediately available. Once pertuzumab-based therapy has been safely established, the physician may determine the suitability of administration of Phesgo outside of the clinical setting (e.g. at home) by a healthcare professional (see section 4.4).

In order to prevent medication errors, it is important to check the vial label to ensure that the medicinal product being prepared and administered is Phesgo.

Patients currently receiving intravenous pertuzumab and trastuzumab can switch to Phesgo. Switching treatment from intravenous pertuzumab and trastuzumab to Phesgo (or vice versa) was investigated in study MO40628 (see sections 4.8 and 5.1).

Posology

Patients treated with Phesgo 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 hybridization (ISH), assessed by a validated test.

To ensure accurate and reproducible results, the testing must be performed in a specialized laboratory, which can ensure validation of the testing procedures. For full instructions on assay performance and interpretation, please refer to the package leaflet of validated HER2 testing assays.

For Phesgo dose recommendations in early and metastatic breast cancer please refer to Table 1.

Table 1: Phesgo recommended dosing and administration

Dose (irrespective of body weight)

Approximate duration of subcutaneous injection

Observation time ab

Loading dose

1200 mg pertuzumab/ 600 mg trastuzumab

8 minutes

30 minutes

Maintenance dose (every 3 weeks)

600 mg pertuzumab/ 600 mg trastuzumab

5 minutes

15 minutes

aPatients should be observed for injection-related reactions and hypersensitivity reactions

bObservation period should start following administration of Phesgo and be completed prior to any subsequent administration of chemotherapy

In patients receiving a taxane, Phesgo should be administered prior to the taxane.

When administered with Phesgo, the recommended initial dose of docetaxel is 75 mg/m2 and subsequently escalated to 100 mg/m2 depending on the chosen regimen and tolerability of the initial dose. Alternatively, docetaxel can be given at 100 mg/m2 on a 3-weekly schedule from the start, again depending on the chosen regimen. If a carboplatin-based regimen is used, the recommended dose for docetaxel is 75 mg/m2 throughout (no dose escalation). When administered with Phesgo in the adjuvant setting, the recommended dose of paclitaxel is 80 mg/m2 once weekly for 12 weekly cycles.

In patients receiving an anthracycline-based regimen, Phesgo should be administered following completion of the entire anthracycline regimen (see section 4.4).

Metastatic breast cancer

Phesgo should be administered in combination with docetaxel. Treatment with Phesgo may continue until disease progression or unmanageable toxicity even if treatment with docetaxel is discontinued (see section 4.4).

Early breast cancer

In the neoadjuvant setting, Phesgo should be administered for 3 to 6 cycles in combination with chemotherapy, as part of a complete treatment regimen for early breast cancer (see section 5.1).

In the adjuvant setting, Phesgo should be administered for a total of one year (up to 18 cycles or until disease recurrence, or unmanageable toxicity, whichever occurs first), as part of a complete regimen for early breast cancer and regardless of the timing of surgery. Treatment should include standard anthracycline- and/or taxane-based chemotherapy. Phesgo should start on Day 1 of the first taxane-containing cycle and should continue even if chemotherapy is discontinued.

Delayed or missed doses

If the time between two sequential injections is:

• less than 6 weeks, the maintenance dose of Phesgo 600 mg/600 mg should be administered as soon as possible. Thereafter, continue with the 3-weekly schedule.

• 6 weeks or more, a loading dose of Phesgo 1200 mg/600 mg should be re-administered followed by maintenance dose of Phesgo 600 mg/600 mg every 3 weeks thereafter.

Dose modifications

Dose reductions are not recommended for Phesgo. Discontinuation of treatment with Phesgo may be needed at the discretion of the physician.

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).

Switching from intravenous pertuzumab and trastuzumab administration to Phesgo

• In patients receiving intravenous pertuzumab and trastuzumab with less than 6 weeks since their last dose, Phesgo should be administered as a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab and every 3 weeks for subsequent administrations.

• In patients receiving intravenous pertuzumab and trastuzumab with 6 weeks or more since their last dose, Phesgo should be administered as a loading dose of 1200 mg pertuzumab/600 mg trastuzumab, followed by a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks for subsequent administrations.

Left ventricular dysfunction

Phesgo should be withheld for at least 3 weeks for any signs and symptoms suggestive of congestive heart failure. Phesgo should be discontinued if symptomatic heart failure is confirmed (see section 4.4 for more details).

Patients with metastatic breast cancer

Patients should have a pre-treatment left ventricular ejection fraction (LVEF) of ≥ 50 %. Phesgo should be withheld for at least 3 weeks for:

• a drop in LVEF to less than 40 %

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

Phesgo may be resumed if the LVEF has recovered to > 45 %, or to 40-45 % associated with a difference of < 10 % points below pre-treatment values.

Patients with early breast cancer

Patients should have a pre-treatment LVEF of ≥ 55 % (≥ 50 % after completion of the anthracycline component of chemotherapy, if given).

Phesgo should be withheld for at least 3 weeks for a drop in LVEF to less than 50 % associated with a fall of ≥ 10 % points below pre-treatment values.

Phesgo may be resumed if the LVEF has recovered to ≥ 50 % or to a difference of < 10 % points below pre-treatment values.

Special populations

Elderly

No overall differences in efficacy of Phesgo were observed in patients ≥ 65 and < 65 years of age. No dose adjustment of Phesgo is required in patients ≥ 65 years of age. Limited data are available in patients > 75 years of age.

Please see section 4.8 for assessment of safety in elderly patients.

Renal impairment

Dose adjustments of Phesgo 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 (PK) data available (see section 5.2).

Hepatic impairment

The safety and efficacy of Phesgo have not been studied in patients with hepatic impairment. Patients with hepatic impairment are unlikely to require Phesgo dose adjustment. No specific dose adjustment are recommended (see section 5.2).

Paediatric population

The safety and efficacy of Phesgo in children and adolescents below 18 years of age have not been established. There is no relevant use of Phesgo in the paediatric population in the indication of breast cancer.

Method of administration

Phesgo should be administered as a subcutaneous injection only. Phesgo is not intended for intravenous administration.

The injection site should be alternated between the left and right thigh only. New injections should be given at least 2.5 cm from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. The dose should not be split between two syringes or between two sites of administration. During the treatment course with Phesgo, other medicinal products for subcutaneous administration should preferably be injected at different sites.

The loading dose and maintenance dose should be administered over 8 and 5 minutes, respectively.

An observation period of 30 minutes after completion of Phesgo loading dose and 15 minutes after completion of the maintenance dose is recommended for injection-related reactions (see sections 4.4 and 4.8).

Injection-related reactions

The injection may be slowed or paused if the patient experiences injection-related symptoms (see section 4.4 and section 4.8). Treatment including oxygen, beta agonists, antihistamines, rapid intravenous fluids and antipyretics may also help alleviate systemic symptoms.

Hypersensitivity reactions /anaphylaxis

The injection 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 and section 4.8).

For instructions on use and handling of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

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).

For administration outside of the clinical setting, appropriate medications for the management of hypersensitivity reactions in line with local standard clinical practice (depending on severity and type of reaction e.g. epinephrine, beta-agonists, antihistamines and corticosteroids) should be available for immediate use.

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 with known effect

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

This medicinal product contains polysorbate 20. Each vial of 10mL solution contains 4.0 mg of polysorbate 20. Each vial of 15 mL solution contains 6.0 mg of polysorbate 20. Polysorbate 20 may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No formal drug interaction studies have been performed.

Pertuzumab

No PK interactions were observed between pertuzumab and trastuzumab, or between pertuzumab 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 pertuzumab and trastuzumab or between pertuzumab and docetaxel. This absence of drug-drug interaction was confirmed by PK data from the NEOSPHERE and APHINITY studies.

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

Trastuzumab

No formal drug interaction studies have been performed. Clinically significant interactions between trastuzumab and the concomitant medicinal products used in clinical trials have not been observed.

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

PK data from studies BO15935 and M77004 in women with HER2-positive metastatic breast cancer suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxylpaclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous, respectively). However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite were unclear.

Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and 2 mg/kg intravenous weekly) and docetaxel (60 mg/m2 intravenous) in Japanese women with HER2-positive metastatic breast cancer, suggested that concomitant administration of trastuzumab had no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.

PK data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.

Effect of antineoplastic agents on trastuzumab pharmacokinetics

By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading/2 mg/kg q1w intravenous) and observed serum concentrations in Japanese women with HER2-positive metastatic breast cancer (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the pharmacokinetics of trastuzumab was found. Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with trastuzumab and paclitaxel and two Phase II studies in which trastuzumab was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab.

Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive metastatic breast cancer were treated concomitantly with trastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the PK of trastuzumab.

The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception

Women of childbearing potential should use effective contraception while receiving Phesgo and for 7 months following the last dose.

Pregnancy

In animal studies pertuzumab has shown reproductive toxicity. There is only a limited amount of data from the use of pertuzumab in pregnant women.

From animal studies, it is not known whether trastuzumab can affect reproductive capacity (see section 5.3). However, in the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some of which resulted in fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab.

Based on the aforementioned animal studies and post-marketing data, Phesgo should therefore be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Phesgo, or if a patient becomes pregnant while receiving Phesgo or within 7 months following the last dose of Phesgo, close monitoring by a multidisciplinary team is desirable.

Breast-feeding

As human IgG is secreted into human milk and the potential for absorption and harm to the infant is unknown, women should not breast-feed during Phesgo therapy and for at least 7 months following the last dose.

Fertility

Pertuzumab

No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of pertuzumab for up to six-month duration in cynomolgus monkeys (see section 5.3).

Trastuzumab

Reproduction studies conducted in cynomolgus monkeys with trastuzumab revealed no evidence of impaired fertility in female cynomolgus monkeys (see section 5.3).

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.

4.8. Undesirable effects

Summary of the safety profile

The most common ADRs (≥ 30 %) reported in patients treated with Phesgo or intravenous pertuzumab in combination with trastuzumab and chemotherapy were alopecia, diarrhoea, nausea, anemia, asthenia and arthralgia.

The most common serious adverse events (SAE) (≥ 1 %) reported in patients treated with Phesgo or intravenous pertuzumab in combination with trastuzumab were febrile neutropenia, cardiac failure, pyrexia, neutropenia, neutropenic sepsis, neutrophil count decreased and pneumonia.

The safety profile of Phesgo was overall consistent to the known safety profile of intravenous pertuzumab in combination with trastuzumab, with an additional ADR of injection site reaction (15.3 % vs. 0.4 %).

In the pivotal trial FEDERICA, SAEs were equally distributed between the Phesgo treatment arm and the intravenous pertuzumab in combination with trastuzumab treatment arm. The following adverse drug reactions were reported with a higher frequency (≥ 5 %) with Phesgo compared to intravenous pertuzumab in combination with trastuzumab: alopecia 79 % vs 73 %, myalgia 27.0 % vs 20.6 %, and dyspnea 12.1 % vs 6 %.

Tabulated list of adverse reactions

The safety of pertuzumab in combination with trastuzumab has been evaluated in 3834 patients with HER2-positive breast cancers in the pivotal trials CLEOPATRA, NEOSPHERE, TRYPHAENA, APHINITY and FEDERICA. It was generally consistent across studies, although the incidence and most common adverse drug reactions (ADRs) varied depending on whether pertuzumab in combination with trastuzumab were administered with or without concomitant anti-neoplastic agents.

Table 2 presents, in the first column, ADRs that have been reported in association with the use of pertuzumab in combination with trastuzumab and chemotherapy in the below mentioned pivotal clinical trials (n= 3834) and in the post-marketing setting. As pertuzumab is used in combination with trastuzumab and chemotherapy, it is difficult to ascertain the causal relationship of an adverse reaction to a particular medicinal product. The two last columns detail ADRs reported in the Phesgo arm of FEDERICA study (n=243) when Phesgo is administered with chemotherapy agent and as monotherapy.

• CLEOPATRA, in which pertuzumab was given in combination with trastuzumab and docetaxel to patients with metastatic breast cancer (n= 453)

• NEOSPHERE (n= 309) and TRYPHAENA (n= 218), in which neoadjuvant pertuzumab was given in combination with trastuzumab and chemotherapy to patients with locally advanced, inflammatory or early breast cancer

• APHINITY, in which adjuvant pertuzumab was given in combination with trastuzumab and anthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patients with early breast cancer (n= 2364)

• FEDERICA, in which Phesgo (n= 243) or intravenous pertuzumab and trastuzumab (n= 247) was firstly administered in combination with chemotherapy (neoadjuvant phase) and subsequently as monotherapy (adjuvant phase) to patients with early breast cancer.

These 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, ADRs are presented in the order of decreasing seriousness.

Table 2 Summary of ADRs in patients treated with pertuzumab, trastuzumab in pivotal clinical trials^, ^^, and in the post-marketing setting†

N = 3834^

N = 243^^

Pertuzumab+trastuzumab

Phesgo with chemotherapy

Phesgo monotherapy

ADR

(MedDRA Preferred Term)

System Organ Class

Frequency category

Frequency category

Frequency category

Blood and lymphatic system disorders

Neutropenia

Very common

Very common

Common

Anemia

Very common

Very common

Common

Febrile neutropenia*

Very common

Common

Not known

Leukopenia

Very common

Common

Common

Cardiac disorders

Left ventricular dysfunction**

Common

Uncommon

Uncommon

Cardiac failure**

Common

Uncommon

Common

Eye disorders

Lacrimation increased

Very common

Common

Uncommon

Gastrointestinal disorders

Diarrhea

Very common

Very common

Very common

Nausea

Very common

Very common

Common

Vomiting

Very common

Very common

Common

Stomatitis

Very common

Very common

Common

Constipation

Very common

Very common

Common

Dyspepsia

Very common

Very common

Common

Abdominal pain

Very common

Common

Common

General disorders and administration site conditions

Fatigue

Very common

Very common

Common

Mucosal inflammation

Very common

Very common

Uncommon

Asthenia

Very common

Very common

Very common

Pyrexia

Very common

Common

Common

Edema peripheral

Very common

Common

Common

Injection site reaction°°°

Very common

Common

Very common

Immune system disorders

Hypersensitivity*°

Common

Uncommon

Not known

Drug hypersensitivity*°

Common

Uncommon

Uncommon

Anaphylactic reaction*°

Uncommon

Not known

Not known

Cytokine release syndrome°

Rare

Not known

Not known

Infections and infestations

Nasopharyngitis

Very common

Common

Common

Upper respiratory tract infection

Common

Common

Common

Paronychia

Common

Common

Common

Metabolism and nutrition disorders

Decreased appetite

Very common

Very common

Common

Tumour lysis syndrome†

Rare

Not known

Not known

Musculoskeletal and connective tissue disorders

Arthralgia

Very common

Very common

Very common

Myalgia

Very common

Very common

Common

Pain in extremity

Very common

Common

Common

Nervous system disorders

Dysgeusia

Very common

Very common

Common

Headache

Very common

Very common

Common

Peripheral sensory neuropathy

Very common

Very common

Common

Neuropathy peripheral

Very common

Very common

Common

Dizziness

Very common

Common

Common

Paraesthesia

Very common

Common

Common

Psychiatric disorders

Insomnia

Very common

Very common

Common

Respiratory, thoracic and mediastinal disorders

Epistaxis

Very common

Very common

Common

Cough

Very common

Very common

Common

Dyspnea

Very common

Common

Common

Interstitial lung disease°°

Uncommon

Not known

Not known

Skin and subcutaneous tissue disorders

Alopecia

Very common

Very common

Uncommon

Rash

Very common

Very common

Common

Dry skin

Very common

Very common

Common

Nail disorder

Very common

Common

Common

Pruritus

Very common

Common

Common

Vascular disorders

Hot flush

Very common

Common

Very common

^ Shows pooled data from the overall treatment period in CLEOPATRA (data cut off 11 February 2014; median number of cycles of pertuzumab was 24); and from the neoadjuvant treatment period in NEOSPHERE (median number of cycles of pertuzumab was 4, across all treatment arms) and TRYPHAENA (median number of cycles of pertuzumab was 3-6 across treatment arms); from the treatment period of APHINITY(median number of cycles of pertuzumab was 18) and from the overall treatment period of FEDERICA (median number of cycles of Phesgo was 18).

^^Shows Phesgo data from the overall treatment period of FEDERICA (median number of cycles of Phesgo was 18)

* Including ADRs with a fatal outcome have been reported.

** For the overall treatment period across the 5 studies (CLEOPATRA, NEOSPHERE, TRYPHAENA, APHINITY, FEDERICA). The incidence of left ventricular dysfunction and cardiac failure congestive reflect the MedDRA Preferred Terms reported in the individual studies.

° Terms that are the most frequently reported in the medical concepts of Anaphylactic reaction and Injection/Infusion-related Reaction which are further described in the Description of selected adverse reactions section.

°° No events of Interstitial lung disease were reported in the FeDeriCa study but these events have been observed with trastuzumab.

°°°Observed with Phesgo only (subcutaneous administration related). The higher frequency observed in the adjuvant phase is related to a longer period of treatment when Phesgo is administered as monotherapy.

† ADRs reported in the post marketing setting of pertuzumab and trastuzumab IV.

Description of selected adverse reactions

Left ventricular dysfunction

Phesgo

In the pivotal trial FEDERICA, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEF decline of at least 10 % points from baseline and to < 50 % was 0.4 % of Phesgo treated patients vs 0 % of intravenous pertuzumab and trastuzumab-treated patients during neoadjuvant phase (when concomitantly administered with chemotherapy). Of the patients who experienced symptomatic heart failure, none of the Phesgo-treated patients had recovered at the data cut-off and one patient was withdrawn from Phesgo due to an event of symptomatic heart failure. The incidences of symptomatic heart failure with a LVEF decline of at least 10 % points from baseline and to < 50 % were similar in the adjuvant (when Phesgo was administered alone) and in the follow-up phases. Asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10 %-points from baseline and to < 50 % (confirmed by secondary LVEF) were not reported in Phesgo-treated patients and were reported in 0.4 % of intravenous pertuzumab and trastuzumab-treated patients during the neoadjuvant phase (see sections 4.2 and 4.4). There was no report of asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10 % -points from baseline and to < 50 % (confirmed by secondary LVEF) in both arms in the adjuvant phase. In the follow up phase, 1.6 % of Phesgo treated patients and 3.6 % of intravenous pertuzumab and trastuzumab-treated patients had this type of cardiac event.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA, the incidence of LVD during study treatment was higher in the placebo-treated group than the pertuzumab-treated group (8.6 % and 6.6 %, respectively). The incidence of symptomatic LVD was also lower in the pertuzumab treated group (1.8 % in the placebo-treated group vs. 1.5 % in the pertuzumab-treated group) (see section 4.4).

In the neoadjuvant trial NEOSPHERE, in which patients received four cycles of pertuzumab as neoadjuvant treatment, the incidence of LVD (during the overall treatment period) was higher in the pertuzumab, 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 pertuzumab 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 pertuzumab plus trastuzumab and FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by pertuzumab plus trastuzumab and docetaxel; 9.3 % in the group treated with pertuzumab plus trastuzumab and docetaxel following FEC; and 6.6 % in the group treated with pertuzumab in combination with TCH (docetaxel, carboplatin and trastuzumab). The incidence of symptomatic LVD (congestive heart failure) was 1.3 % in the group treated with pertuzumab plus trastuzumab and docetaxel following FEC (this excludes a patient who experienced symptomatic LVD during FEC treatment prior to receiving pertuzumab plus trastuzumab and docetaxel) and also 1.3 % in the group treated with pertuzumab in combination with TCH. No patients in the group treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel experienced symptomatic LVD.

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 doxorubicin and cyclophosphamide (AC) followed by pertuzumab plus trastuzumab and paclitaxel and none of the patients (0 %) experienced symptomatic LVD in the group treated with FEC followed by pertuzumab 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 pertuzumab plus trastuzumab and paclitaxel and 3.5 % in the group treated with FEC followed by pertuzumab plus trastuzumab and docetaxel.

In APHINITY, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEF decline of at least 10 % points from baseline and to < 50 % was < 1 % (0.6 % of pertuzumab-treated patients vs 0.3 % of placebo-treated patients). Of the patients who experienced symptomatic heart failure, 46.7 % of pertuzumab-treated patients and 57.1 % of placebo-treated patients had recovered (defined as 2 consecutive LVEF measurements above 50 %) at the data cutoff. The majority of the events were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10 % points from baseline and to < 50 % were reported in 2.7 % of pertuzumab-treated patients and 2.8 % of placebo-treated patients, of whom 79.7 % of pertuzumab-treated patients and 80.6 % of placebo-treated patients had recovered at the data cutoff.

Injection/infusion-related reactions

Phesgo

In the pivotal trial FEDERICA, an injection/infusion-related reaction was defined as any systemic reaction reported within 24 hours of Phesgo or intravenous pertuzumab in combination with trastuzumab administration (see sections 4.2 and 4.4).

Injection-related reactions were reported in0.4 % of Phesgo treated patients and infusion related reactions were reported in 10.7 % of intravenous pertuzumab and trastuzumab-treated patients in the neoadjuvant phase . In the adjuvant phase, there were no injection-related reactions reported in Phesgo -treated patients, and infusion related reactions were reported in 1.6 % of intravenous pertuzumab and trastuzumab-treated patients. Most of the systemic injection/infusion related reactions seen with Phesgo or intravenous pertuzumab and trastuzumab were chills, nauseaor vomiting.

Injection site reactions defined as any local reaction reported within 24 hours of Phesgo administration, were reported in 6.9 %, and in 12.9 % of Phesgo treated patients in the neoadjuvant phase and the adjuvant phase, respectively, and were all grade 1 or 2 events. Most of the local injection site reactions seen with Phesgo were either injection site pain or injection site erythema.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

An administration-related reaction was defined in the pivotal trials 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 pertuzumab was given the day before trastuzumab and docetaxel to allow for the examination of pertuzumab associated reactions. On the first day when only pertuzumab was administered, the overall frequency of infusion-related reactions was 9.8 % in the placebo-treated group and 13.2 % in the pertuzumab-treated group, with the majority of reactions being mild or moderate. The most common infusion-related reactions (≥ 1.0 %) in the pertuzumab-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 related reactions (≥ 1.0 %) in the pertuzumab-treated group were fatigue, drug hypersensitivity, dysgeusia, hypersensitivity, myalgia, and vomiting (see section 4.4).

In neoadjuvant and adjuvant trials, pertuzumab was administered on the same day as the other study treatment. Infusion-related reactions occurred in 18.6 %-25.0 % of patients on the first day of pertuzumab administration (in combination with trastuzumab and chemotherapy). The type and severity of events were consistent with those observed in CLEOPATRA, with a majority of reactions being mild or moderate in severity.

Hypersensitivity reactions/anaphylaxis

Phesgo

In the pivotal trial FEDERICA, the overall frequency of hypersensitivity/anaphylaxis reported events related to HER2-targeted therapy was 1.2 % in the Phesgo-treated patients vs. 0.8 % in the intravenous pertuzumab and trastuzumab-treated patients, of which none were NCI-CTCAE (version 4.0) grade 3-4 (see section 4.4). One patient experienced a hypersensitivity/anaphylaxis event during or immediately after administration of Phesgo; at the first cycle which led to withdrawal from therapy (see sections 4.2 and 4.4).

During the neoadjuvant phase, 0.4% of Phesgo treated patients and 0.4% of intravenous pertuzumab and trastuzumab-treated patients had drug hypersensitivity. During the adjuvant phase, 0.4 % of Phesgo treated patients had drug hypersensitivity, and none of the intravenous pertuzumab and trastuzumab-treated patients had hypersensitivity or drug hypersensitivity.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

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 pertuzumab-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 pertuzumab-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 the neoadjuvant and adjuvant trials, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In NEOSPHERE, two patients in the pertuzumab and docetaxel-treated group experienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overall frequency of hypersensitivity/anaphylaxis was highest in the pertuzumab and TCH treated group (13.2 % and 7.6 %, respectively), of which 2.6 % and 1.3 % of events, respectively, were NCI-CTCAE Grade 3-4.

Febrile neutropenia

Phesgo

In the pivotal trial FEDERICA, febrile neutropenia (Grade 3 or 4) occurred in 6.6 % of Phesgo treated patients and 5.6 % of intravenous pertuzumab and trastuzumab-treated patients during the neoadjuvant phase. No febrile neutropenia events (Grade 3 or 4) occurred during the adjuvant phase.

As in intravenous pertuzumab and trastuzumab pivotal trials, a higher incidence of febrile neutropenia (Grade 3 or 4) was observed among intravenous pertuzumab and trastuzumab -treated Asian patients (13.0 %), similarly, the incidence of febrile neutropenia in Phesgo-treated Asian patients was also higher (13.7 %) during the neoadjuvant phase. During the adjuvant phase, no events of febrile neutropenia (Grade 3 or 4) were observed in either arm.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

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 pertuzumab-treated group and 58.3 % of patients in the placebo-treated group), of which the majority were neutropenic events (see section 4.4). Febrile neutropenia occurred in 13.7 % of pertuzumab-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 among 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 Pertuzumab-treated group (25.8 %) compared with the placebo-treated group (11.3 %).

In the NEOSPHERE trial, 8.4 % of patients treated with neoadjuvant pertuzumab, 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 pertuzumab + TCH, and 9.3 % of patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel following FEC. In TRYPHAENA, the incidence of febrile neutropenia was higher in patients who received six cycles of pertuzumab compared with patients who received three cycles of pertuzumab, 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 pertuzumab, trastuzumab and docetaxel experienced febrile neutropenia compared with 4.0 % of Asian patients treated with neoadjuvant trastuzumab and docetaxel.

In the APHINITY trial, febrile neutropenia occurred in 12.1 % of pertuzumab-treated patients and 11.1 % of placebo-treated patients. As in the CLEOPATRA, TRYPHAENA, and NEOSPHERE trials, a higher incidence of febrile neutropenia was observed among pertuzumab-treated Asian patients compared with other races in the APHINITY trial (15.9 % of pertuzumab-treated patients and 9.9 % of placebo-treated patients).

Diarrhoea

Phesgo

In the pivotal trial FEDERICA during the neoadjuvant phase, diarrhoea occurred in 60.5% of Phesgo-treated patients and 54.8% of intravenous pertuzumab and trastuzumab-treated patients. Grade ≥ 3 diarrhoea was reported in 6.6 % of patients in the Phesgo arm vs.4.0 % in the intravenous pertuzumab and trastuzumab arm (see section 4.4).

During the adjuvant phase, diarrhoea occurred in 17.7 % of Phesgo-treated patients and 20.6 % of intravenous pertuzumab and trastuzumab-treated patients. Grade ≥ 3 diarrhoea was reported in 0 % of patients in the Phesgo arm vs. 1.2 % in the intravenous pertuzumab and trastuzumab arm.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA in metastatic breast cancer, diarrhoea occurred in 68.4 % of pertuzumab-treated patients and 48.7 % of placebo-treated patients (see section 4.4). 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 pertuzumab-treated patients vs. 5.1 % in placebo-treated patients. The median duration of the longest episode was 18 days in pertuzumab-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 pertuzumab, 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 pertuzumab+TCH and 61.4 % of patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel following FEC. In both studies most events were mild to moderate in severity.

In the APHINITY trial, a higher incidence of diarrhoea was reported in the pertuzumab-treated arm (71.2 %) compared to the placebo arm (45.2 %). Grade ≥ 3 diarrhoea was reported in 9.8 % of patients in the pertuzumab arm vs. 3.7 % in the placebo arm. The majority of the reported events were Grade 1 or 2 in severity. The highest incidence of diarrhoea (all Grades) was reported during the targeted therapy+ taxane chemotherapy period (61.4 % of patients in the pertuzumab arm vs. 33.8 % of patients in the placebo arm). The incidence of diarrhoea was much lower after chemotherapy cessation, affecting 18.1 % of patients in the pertuzumab arm vs. 9.2 % of patients in the placebo arm in the post-chemotherapy targeted therapy period.

Rash

Phesgo

In the pivotal trial FEDERICA rash occurred in 10.7 % of Phesgo-treated patients and 15.5 % of intravenous pertuzumab and trastuzumab-treated patients during the neoadjuvant phase. During the adjuvant phase, rash occurred in 8.2 % of Phesgo-treated patients and 8.7 % of intravenous pertuzumab and trastuzumab-treated patients. The majority of rash events were Grade 1 or 2.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA in metastatic breast cancer, rash occurred in 51.7 % of pertuzumab-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 pertuzumab, 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 pertuzumab + TCH and 20.0 % of patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel following FEC. The incidence of rash was higher in patients who received six cycles of pertuzumab compared with patients who received three cycles of pertuzumab, independent of the chemotherapy given.

In the APHINITY trial, the adverse reaction of rash occurred in 25.8 % of patients in pertuzumab arm vs. 20.3 % of patients in placebo arm. The majority of rash events were Grade 1 or 2.

Laboratory abnormalities

Phesgo

In the pivotal trial FEDERICA, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was balanced in the two treatment groups (13.6 % of Phesgo -treated patients and 13.9 % of intravenous pertuzumab and trastuzumab-treated patients) during the neoadjuvant phase and were significantly lower during the adjuvant phase (0.8% of Phesgo -treated patients and 0% of intravenous pertuzumab and trastuzumab-treated patients).

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA in metastatic breast cancer, the incidence of NCI-CTCAE v.3 Grade 3-4 neutropenia was balanced in the two treatment groups (86.3 % of pertuzumab-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 pertuzumab, 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 neoadjuvant pertuzumab+ TCH and 77.0 % in patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel following FEC, including 66.7 % and 59.5 % Grade 4 neutropenia, respectively.

In the APHINITY trial, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was 40.6 % in patients treated with pertuzumab, trastuzumab and chemotherapy compared with 39.1 % in patients treated with placebo, trastuzumab and chemotherapy, including 28.3 % and 26.5 % Grade 4 neutropenia, respectively.

Immunogenicity

As with all therapeutic proteins, there is the potential for an immune response to pertuzumab and trastuzumab in patients treated with Phesgo.

In the FEDERICA study, the incidence of treatment-emergent anti-pertuzumab and anti-trastuzumab antibodies was 10.6 % (26/245) and 0.4 % (1/245), respectively, in patients treated with intravenous pertuzumab and trastuzumab. Among patients that tested positive to anti-pertuzumab antibodies, neutralizing anti-pertuzumab antibodies were detected in three patients.

The incidence of treatment-emergent anti-pertuzumab, anti-trastuzumab, and anti-vorhyaluronidase alfa antibodies was 12.9 % (31/241), 2.1 % (5/241), and 6.3 % (15/238), respectively, in patients treated with Phesgo. Among these patients, neutralizing anti-pertuzumab antibodies were detected in two patients, and neutralizing anti-trastuzumab antibodies were detected in one patient.

The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or anti-vorhyaluronidase alfa antibodies after treatment with Phesgo is unknown.

Switching treatment from intravenous pertuzumab and trastuzumab to Phesgo (or vice versa)

Study MO40628 investigated the safety of switching between intravenous pertuzumab and trastuzumab and Phesgo subcutaneous (Arm A) and vice versa (Arm B) with a primary objective to evaluate patient preference for Phesgo (see section 5.1 for study design details).

Among the patients in Arm A, the incidence of AEs during Cycles 1-3 (intravenous treatment) was 77.5 % (62/80 patients) compared to Cycles 4-6 (subcutaneous treatment) which was 72.5 % (58/80 patients). Among the patients in Arm B, the incidence of AEs during Cycles 1-3 (subcutaneous treatment) was 77.5 % (62/80 patients) compared to Cycles 4-6 (intravenous treatment) which was 63.8 % (51/80 patients), mainly due to higher incidence of local injection site reactions (all grade 1 or 2) during Phesgo administration. Pre-switching rates (Cycles 1-3) for serious adverse events, grade 3 adverse events and treatment discontinuations due to adverse events were low (<6 %) and similar to post-switching rates (Cycles 4-6).

No grade 4 or grade 5 adverse events were reported.

Elderly patients

In FEDERICA, no overall differences in safety of Phesgo were observed in patients ≥ 65 and < 65 years of age.

However, in the pivotal pertuzumab clinical trials with intravenous pertuzumab in combination with trastuzumab, decreased appetite, anaemia, weight decreased, asthenia, dysgeusia, neuropathy peripheral, hypomagnesemia and diarrhoea, occurred with an incidence of ≥ 5 % higher in patients ≥ 65 years of age (n= 418) compared to patients < 65 years of age (n= 2926).

Limited clinical trial data are available in patients > 75 years of age treated with Phesgo or intravenous pertuzumab and trastuzumab. Post-marketing data shows no differences in safety of pertuzumab in combination with trastuzumab in patients ≥ 65 and < 65 years of age.

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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest Phesgo dose tested is 1200 mg pertuzumab/600 mg trastuzumab. In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.