Summary of the safety profileThe safety of Perjeta has been evaluated in more than 1,400 patients either in the pivotal trial CLEOPATRA or in phase I and phase II trials conducted in patients with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic agents. In the pivotal clinical trial CLEOPATRA, 408 patients received at least one dose of Perjeta in combination with trastuzumab and docetaxel. The most common adverse drug reactions (ADRs) (≥ 50%) were diarrhoea, alopecia and neutropenia. The most common NCI-CTCAE (version 3) Grade 3-4 ADRs (> 10%) were neutropenia, febrile neutropenia and leucopenia, and the most common serious adverse events were febrile neutropenia, neutropenia and diarrhoea. Treatment-related deaths occurred in 1.2% of patients in the Perjeta-treated group and 1.5% of patients in the placebo-treated group and were mainly due to febrile neutropenia and/or infection.
Tabulated list of adverse reactionsTable 1 summarizes the ADRs from the pivotal clinical trial CLEOPATRA, in which Perjeta was given in combination with docetaxel and trastuzumab. As Perjeta is used with trastuzumab and docetaxel, it is difficult to ascertain the causal relationship of an adverse event to a particular medicinal product. The safety of Perjeta in phase I and phase II studies was generally consistent with that observed in the CLEOPATRA trial, though the incidence and most common ADRs varied depending on whether Perjeta was administered as monotherapy or with concomitant anti-neoplastic agents. 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, adverse reactions are presented in the order of decreasing seriousness.
Table 1 Summary of ADRs from the pivotal clinical trial CLEOPATRA
* Including adverse reactions with a fatal outcome. Except for febrile neutropenia, neutropenia, leucopenia, lacrimation increased, interstitial lung disease, paronychia, and alopecia, all events in this table were also reported in at least 1% of patients participating in Perjeta monotherapy trials, although not necessarily considered causally related to Perjeta by the investigator. Very common events (reported in ≥ 10% of Perjeta monotherapy-treated patients) are marked in the Table with a .° Hypersensitivity/anaphylactic reaction is based on a group of terms.°° Infusion reaction/cytokine release syndrome includes a range of different terms within a time window, see Description of selected adverse reactions below.
|System organ class ||Very Common||Common||Uncommon|
|Infections and infestations
||Upper respiratory tract infection
|Blood and lymphatic system disorders
|| || |
|Immune system disorders
||Hypersensitivity/ anaphylactic reaction°Infusion reaction/cytokine release syndrome°°|| || |
|Metabolism and nutrition disorders
||Decreased appetite || || |
|| || |
|Nervous system disorders
Peripheral sensory neuropathy
|| || |
|| || |
|| ||Left ventricular dysfunction (including congestive heart failure)
|Respiratory, thoracic and mediastinal disorders
||Dyspnoea Cough ||Pleural effusion
||Interstitial lung disease
||Diarrhoea Vomiting Stomatitis
Nausea Constipation Dyspepsia
|| || |
|Skin and subcutaneous tissue disorders
Rash Nail disorder
|| || |
|Musculoskeletal and connective tissue disorders
|| || |
|General disorders and administration site conditions
Pain Oedema Pyrexia
Fatigue Asthenia ||Chills
ADRs reported in patients receiving Perjeta and trastuzumab after discontinuation of docetaxelIn the pivotal trial CLEOPATRA, ADRs were reported less frequently after discontinuation of docetaxel treatment. After discontinuation of docetaxel, ADRs in the Perjeta and trastuzumab treated group occurred in < 10% of patients with the exception of diarrhoea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), nasopharyngitis (17.0%), asthenia (13.4%), pruritus (13.7%), arthralgia (11.4%), nausea (12.7%), pain in extremity (13.4%), back pain (12.1%) and cough (12.1%).
Description of selected adverse reactions
Left ventricular dysfunctionIn the pivotal trial CLEOPATRA, 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).
Infusion reactionsAn infusion reaction was defined in the pivotal trial CLEOPATRA 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, hypersensitivity, myalgia and vomiting (see section 4.4).
Hypersensitivity reactions/anaphylaxisIn the pivotal trial CLEOPATRA, 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.
Febrile neutropeniaIn 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. 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 for 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%).
DiarrhoeaIn the pivotal clinical trial CLEOPATRA, diarrhoea occurred in 68.4% of Perjeta-treated patients and 48.7% of placebo-treated patients. Most events were mild-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.
RashRash 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.
Laboratory abnormalitiesThe incidence of NCI-CTCAE (version 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).
Reporting of suspected adverse reactionsReporting 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 (see details below).
IrelandHPRA PharmacovigilanceEarlsfort Terrace IRL - Dublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: www.hpra.iee-mail: email@example.com
Malta ADR ReportingWebsite: www.medicinesauthority.gov.mt/adrportal
United KingdomYellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard