Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
The safety of Perjeta has been evaluated in more than 6,000 patients in Phase I, II, and III trials in patients with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic agents. Those studies included the pivotal trials CLEOPATRA (n=808), NEOSPHERE (n=417), TRYPHAENA (n=225), and APHINITY (n=4804) [pooled in Table 2]. The safety of Perjeta was generally consistent across studies, although the incidence and most common adverse drug reactions (ADRs) varied depending on whether Perjeta was administered as monotherapy or with concomitant anti-neoplastic agents.

Tabulated list of adverse reactions

Table 2 summarizes the ADRs from the Perjeta-treated groups of the following pivotal clinical trials: • CLEOPATRA, in which Perjeta was given in combination with docetaxel and trastuzumab to patients with metastatic breast cancer (n=453)

•    NEOSPHERE (n=309) and TRYPHAENA (n=218), in which neoadjuvant Perjeta was given in combination with trastuzumab and chemotherapy to patients with locally advanced, inflammatory, or early breast cancer
•    APHINITY, in which adjuvant Perjeta was given in combination with trastuzumab and anthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patients with early breast cancer (n=2364)

In addition, ADRs reported in the post-marketing setting are included in Table 2. As Perjeta was used with trastuzumab and chemotherapy in these trials, it is difficult to ascertain the causal relationship of an adverse event to a particular medicinal product.

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, ADRs are presented in the order of decreasing seriousness.

The most common ADRs (≥30%) from this pooled data were diarrhoea, alopecia, nausea, fatigue, neutropenia, and vomiting. The most common NCI-CTCAE Grade 3-4 ADRs (≥10%) were neutropenia and febrile neutropenia.

Table 2        Summary of ADRs in patients treated with Perjeta in clinical trials^, and in the Post- marketing setting†


System organ class                Very Common                 Common                   Uncommon                       Rare 
Infections and infestations   Nasopharyngitis          Paronychia
Upper respiratory tract infection

Blood and lymphatic           Febrile neutropenia* system                        Neutropenia disorders                     Leucopenia
Anaemia
Immune system disorders       Infusion reaction°°, *   Hypersensitivity°, *      Anaphylactic reaction°,     Cytokine release Drug hypersensitivity°,   *                           syndrome°°
*
Metabolism and nutrition      Decreased appetite                                                             Tumour lysis disorders                                                                                                    syndrome† Psychiatric disorders         Insomnia
Nervous system disorders      Neuropathy peripheral
Headache
Dysgeusia
Peripheral sensory neuropathy
Dizziness
Paraesthesia
Eye disorders                 Lacrimation increased
Cardiac disorders                                      Left ventricular          Cardiac failure dysfunction **            congestive**
Vascular disorders            Hot flush
Respiratory, thoracic and     Cough                                              Interstitial lung disease mediastinal disorders         Epistaxis                                          Pleural effusion Dyspnoea
Gastrointestinal disorders    Diarrhoea
Vomiting

System organ class                 Very Common                  Common                    Uncommon                       Rare 
Stomatitis
Nausea
Constipation
Dyspepsia
Abdominal pain
Skin and subcutaneous          Alopecia tissue disorders               Rash
Nail disorder
Pruritus
Dry skin
Musculoskeletal and            Myalgia connective tissue disorders Arthralgia
Pain in extremity
General disorders and          Mucosal inflammation Chills administration site            Oedema peripheral          Pain conditions                     Pyrexia                    Oedema
Fatigue
Asthenia
^
Table 2 shows pooled data from the overall treatment period in CLEOPATRA (data cutoff 11 February 2014; median number of cycles of Perjeta was 24); and from the neoadjuvant treatment period in NEOSPHERE (median number of cycles of Perjeta was 4, across all treatment arms) and TRYPHAENA (median number of cycles of Perjeta was 3 – 6 across treatment arms) and from the treatment period of APHINITY (median number of cycles of Perjeta was 18).

* ADRs with a fatal outcome have been reported.
** For the overall treatment period across the 4 studies. The incidence of left ventricular dysfunction and cardiac failure congestive reflect the MedDRA Preferred Terms reported in the individual studies.
° Hypersensitivity/anaphylactic reaction is based on a group of terms.
°° Infusion reaction includes a range of different terms within a time window, see “Description of selected adverse reactions” below.
† ADRs reported in the post marketing setting-

Description of selected adverse reactions

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

In the neoadjuvant trial NEOSPHERE, in which patients received 4 cycles of Perjeta as neoadjuvant treatment, the incidence of LVD (during the overall treatment period) was higher in the Perjeta, 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 Perjeta 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 Perjeta plus trastuzumab and FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by Perjeta plus trastuzumab and docetaxel; 9.3% in the group treated with Perjeta plus trastuzumab and docetaxel following FEC; and 6.6% in the group treated with Perjeta in combination with TCH (docetaxel, carboplatin and trastuzumab). The incidence of symptomatic LVD (congestive heart failure) was 1.3% in the group treated with Perjeta plus trastuzumab and docetaxel following FEC (this excludes a patient who experienced symptomatic LVD during FEC treatment prior to receiving Perjeta plus trastuzumab and docetaxel) and also 1.3% in the group treated with Perjeta in combination with TCH. No patients in the group treated with Perjeta plus trastuzumab and FEC followed by Perjeta 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 Perjeta plus trastuzumab and paclitaxel and none of the patients (0%) experienced symptomatic LVD in the group treated with FEC followed by Perjeta 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 
Perjeta plus trastuzumab and paclitaxel and 3.5% in the group treated with FEC followed by Perjeta 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% (0.8% of Perjeta-treated patients vs 0.4% of placebo- treated patients). Of the patients who experienced symptomatic heart failure, 62.5% of Perjeta-treated patients and 66.7% 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 Perjeta-treated patients and 2. 9% of placebo-treated patients, of whom 84.4% of Perjeta-treated patients and 87.0% of placebo-treated patients had recovered at the data cutoff.

Infusion reactions
An infusion 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 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 13.2% 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, drug hypersensitivity, myalgia and vomiting (see section 4.4).

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

Hypersensitivity reactions/anaphylaxis
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 Perjeta-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 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.

In the neoadjuvant and adjuvant trials, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In NEOSPHERE, two patients in the Perjeta and docetaxel-treated group experienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overall frequency of hypersensitivity/anaphylaxis was highest in the Perjeta 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
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 Perjeta-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 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 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 Perjeta-treated group (25.8%) compared with the placebo-treated group (11.3%).


In the NEOSPHERE trial, 8.4% of patients treated with neoadjuvant Perjeta, 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 Perjeta + TCH, and 9.3% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel following FEC. In TRYPHAENA, the incidence of febrile neutropenia was higher in patients who received six cycles of Perjeta compared with patients who received three cycles of Perjeta, 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 Perjeta, 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 Perjeta-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 Perjeta-treated Asian patients compared with other races in the APHINITY trial (15.9% of Perjeta-treated patients and 9.9% of placebo-treated patients).

Diarrhoea
In the pivotal trial CLEOPATRA in metastatic breast cancer, diarrhoea occurred in 68.4% of Perjeta-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 Perjeta-treated patients vs 5.1% in placebo-treated patients. The median duration of the longest episode was 18 days in Perjeta-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 Perjeta, 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 Perjeta+TCH and 61.4% of patients treated with neoadjuvant Perjeta, 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 Perjeta-treated arm (71.2%) compared to the placebo arm (45.2%). Grade ≥ 3 diarrhoea was reported in 9.8% of patients in the Perjeta 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 Perjeta 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 Perjeta arm vs.
9.2% of patients in the placebo arm in the post-chemotherapy targeted therapy period.

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

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

Laboratory abnormalities
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 Perjeta-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 Perjeta, 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 Perjeta + TCH and 77.0% in patients treated with neoadjuvant Perjeta, 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 Perjeta, 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.

Elderly Patients

The incidence of the following all grade adverse events was at least 5% higher in patients ≥ 65 years of age, compared to patients < 65 years of age: decreased appetite, anaemia, weight decreased, asthenia, dysgeusia, peripheral neuropathy, hypomagnesemia and diarrhoea. Limited data are available in patients > 75 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.
Any suspected adverse events should be reported to the Ministry of Health according to the national regulation by using the form https://sideeffects.health.gov.il/