Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
The safety of trastuzumab emtansine has been evaluated in 2,611 breast cancer patients in clinical studies. In this patient population:

•     the most common serious ADRs (> 0.5% of patients) were haemorrhage, pyrexia, thrombocytopenia, dyspnoea, abdominal pain, musculoskeletal pain, and vomiting.
•     the most common adverse drug reactions (ADRs) (≥25%) with trastuzumab emtansine were nausea, fatigue, musculoskeletal pain, haemorrhage, headache, transaminases increased, thrombocytopenia, and peripheral neuropathy. The majority of ADRs reported were of Grade 1 or 2 severity.
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•     the most common National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≥ 3 ADRs (> 2%) were thrombocytopenia, increased transaminases, anaemia, neutropenia, fatigue and hypokalaemia.

Tabulated list of adverse reactions

The ADRs in 2,611 patients treated with trastuzumab emtansine are presented in Table 3. The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as 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) and not known (cannot be estimated from the available data). Within each frequency grouping and SOC, adverse reactions are presented in order of decreasing seriousness. ADRs were reported using NCI-CTCAE for assessment of toxicity.

Table 3       Tabulated list of ADRs in patients treated with trastuzumab emtansine in clinical trials

System Organ Class        Very Common                  Common                Uncommon Infections and infestationsUrinary tract infection
Blood and lymphatic system Thrombocytopenia,         Neutropenia,
disorders                  Anaemia                   Leucopoenia

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System Organ Class            Very Common              Common                Uncommon Immune system disorders                               Drug hypersensitivity Metabolism and nutrition                              Hypokalaemia disorders
Psychiatric disorders          Insomnia
Nervous system disorders       Neuropathy             Dizziness,
peripheral, Headache   Dysgeusia, Memory impairment
Eye disorders                                         Dry eye,
Conjunctivitis,
Vision blurred,
Lacrimation increased
Cardiac disorders                                     Left ventricular dysfunction
Vascular disorders             Haemorrhage            Hypertension
Respiratory, thoracic and      Epistaxis, Cough,                              Pneumonitis (ILD) mediastinal disorders          Dyspnoea
Gastrointestinal disorders     Stomatitis,            Dyspepsia, Gingival Diarrhoea, Vomiting,   bleeding
Nausea,
Constipation, Dry mouth, Abdominal pain
Hepatobiliary disorders        Transaminases          Blood alkaline          Hepatotoxicity, increased              phosphatase             Hepatic failure,
increased, Blood        Nodular bilirubin increased     regenerative hyperplasia, Portal hypertension
Skin and subcutaneous                                 Rash, Pruritus, tissue disorders                                      Alopecia, Nail disorder, Palmar- plantar erythrodysaesthesia syndrome, Urticaria
Musculoskeletal and            Musculoskeletal connective tissue disorders    pain, Arthralgia,
Myalgia
General disorders and          Fatigue, Pyrexia,      Peripheral oedema,      Injection site administration site            Asthenia               Chills                  extravasation conditions
Injury, poisoning and                                 Infusion-related        Radiation procedural complications                              reactions               pneumonitis 
Table 3 shows pooled data from the overall treatment period in the MBC studies (N= 1871; median number of cycles of trastuzumab emtansine was 10) and in KATHERINE (N=740; median number of cycles was 14).

Description of selected adverse reactions

Thrombocytopenia
Thrombocytopenia or decreased platelet counts were reported in 24.9% of patients in MBC clinical studies with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation (2.6%). Thrombocytopenia was reported in 28.5% of patients in EBC clinical studies 
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with trastuzumab emtansine and was the most common reported adverse reaction for all grades and grades ≥ 3, as well as the most common adverse reaction leading to treatment discontinuation (4.2%), dose interruptions, and dose reductions. The majority of the patients had Grade 1 or 2 events (≥ 50,000/mm3), with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000/mm3) by the next scheduled dose. In clinical studies, the incidence and severity of thrombocytopenia were higher in Asian patients. Independent of race, the incidence of Grade 3 or 4 events (< 50,000/mm3) was 8.7% in patients with MBC treated with trastuzumab emtansine and 5.7% in patients with EBC. For dose modifications for thrombocytopenia, see sections 4.2 and 4.4.

Haemorrhage
Haemorrhagic events were reported in 34.8% of patients in MBC clinical trials with trastuzumab emtansine and the incidence of severe haemorrhagic events (Grade ≥3) occurred in 2.2%.
Haemorrhagic events were reported in 29% of patients with EBC and the incidence of severe haemorrhagic events (Grade ≥3) was 0.4%, including one Grade 5 event. In some of the observed cases the patients had thrombocytopenia, or were also receiving anti-coagulant therapy or antiplatelet therapy; in others there were no known additional risk factors. Cases of bleeding events with a fatal outcome have been observed in both MBC and EBC.

Transaminases increased (AST/ALT)
Increase in serum transaminases (Grade 1-4) has been observed during treatment with trastuzumab emtansine in clinical studies (see section 4.4). Transaminase elevations were generally transient. A cumulative effect of trastuzumab emtansine on transaminases has been observed, and generally recovered when treatment was discontinued. Increased transaminases were reported in 24.2% of patients in MBC clinical studies. Grade 3 or 4 increased AST and ALT were reported in 4.2% and 2.7% of patients with MBC respectively and usually occurred in the early treatment cycles (1-6).
Increased transaminases were reported in 32.4% of patients with EBC. Grade 3 and 4 increased transaminases were reported in 1.5% of patients with EBC. In general, the Grade ≥ 3 hepatic events were not associated with poor clinical outcome; subsequent follow-up values tended to show improvement to ranges allowing the patient to remain on study and continue to receive study treatment at the same or reduced dose. No relationship was observed between trastuzumab emtansine exposure (AUC), trastuzumab emtansine maximum serum concentration (Cmax), total trastuzumab exposure (AUC), or Cmax of DM1 and increases in transaminase. For dose modifications in the event of increased transaminases, see sections 4.2 and 4.4.

Left ventricular dysfunction
Left ventricular dysfunction was reported in 2.2% of patients in MBC clinical studies with trastuzumab emtansine. The majority of events were asymptomatic Grade 1 or 2 decrease in LVEF.
Grade 3 or 4 events were reported in 0.4% of patients with MBC. In an observational study (BO39807), approximately 22% (7 out of 32) of MBC patients initiating trastuzumab emtansine with LVEF of 40-49% at baseline, experienced a LVEF drop of >10% from baseline and/or CHF; most of these patients had other cardiovascular risk factors. Left ventricular dysfunction occurred in 3.0% of patients with EBC, with Grade 3 or 4 in 0.5% of patients. For dose modifications in the event of LVEF decrease, see Table 2 in section 4.2 and section 4.4.

Peripheral neuropathy
Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of trastuzumab emtansine. In patients with MBC, the overall incidence of peripheral neuropathy was 29.0% and 8.6% for Grade ≥ 2. In patients with EBC, the overall incidence was 32.3% and 10.3% for
Grade ≥ 2.

Infusion-related reactions
Infusion-related reactions are characterised by one or more of the following symptoms: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm and tachycardia. Infusion-related reactions were reported in 4.0% of patients in MBC clinical studies with trastuzumab emtansine, with six Grade 3 and no Grade 4 events reported. Infusion-related reactions were reported in 1.6% of patients with EBC, with no Grade 3 or 4 events reported. Infusion-related reactions resolved over the 
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course of several hours to a day after the infusion was terminated. No dose relationship was observed in clinical studies. For dose modifications in the event of infusion-related reactions, see sections 4.2 and 4.4.

Hypersensitivity reactions
Hypersensitivity was reported in 2.6% of patients in MBC clinical studies with trastuzumab emtansine, with one Grade 3 and one Grade 4 events reported. Hypersensitivity was reported in 2.7% of patients with EBC, with Grade 3 or 4 in 0.4% of patients. Overall, the majority of hypersensitivity reactions were mild or moderate in severity and resolved upon treatment. For dose modifications in the event of hypersensitivity reactions, see sections 4.2 and 4.4.

Immunogenicity
As with all therapeutic proteins, there is the potential for an immune response to trastuzumab emtansine. A total of 1243 patients from seven clinical studies were tested at multiple time points for anti-drug antibody (ADA) responses to trastuzumab emtansine. Following trastuzumab emtansine dosing, 5.1% (63/1243) of patients tested positive for anti-trastuzumab emtansine antibodies at one or more post-dose time points. In the Phase I and Phase II studies, 6.4% (24/376) of patients tested positive for anti- trastuzumab emtansine antibodies. In the EMILIA study (TDM4370g/BO21977), 5.2% (24/466) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 13 were also positive for neutralizing antibodies. In the KATHERINE (BO27938) study, 3.7% (15/401) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 5 were also positive for neutralizing antibodies. Due to the low incidence of ADA, conclusions cannot be made on the impact of anti- trastuzumab emtansine antibodies on the pharmacokinetics, safety, and efficacy of trastuzumab emtansine.

Extravasation
Reactions secondary to extravasation have been observed in clinical studies with trastuzumab emtansine. These reactions were usually mild or moderate and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. These reactions have been observed more frequently within 24 hours of infusion. In the post-marketing setting, cases of epidermal injury or necrosis following extravasation have been exceptionally observed within days to weeks after infusion.
Specific treatment for trastuzumab emtansine extravasation is unknown at this time (see section 4.4).

Laboratory abnormalities

Tables 4 and 5 displays laboratory abnormalities observed in patients treated with trastuzumab emtansine in clinical study TDM4370g/BO21977/EMILIA and study BO27938/KATHERINE.



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Table 4    Laboratory abnormalities observed in patients treated with trastuzumab emtansine in study TDM4370g/BO21977/EMILIA

Trastuzumab emtansine (N=490)
All
Parameter                    Grades (%)    Grade 3 (%)    Grade 4 (%) Hepatic
Increased bilirubin                                 21             <1                0 Increased AST                                       98             8                 <1 Increased ALT                                       82             5                 <1 Haematologic
Decreased platelet count                            85             14                3 Decreased haemoglobin                               63              5                1 Decreased neutrophils                               41              4                <1 Potassium
Decreased potassium                                 35              3                <1 
Table 5    Laboratory abnormalities observed in patients treated with trastuzumab emtansine in study BO27938/KATHERINE

Trastuzumab emtansine (N=740)
Parameter                   All Grade %     Grade 3 (%)    Grade 4 (%) Hepatic
Increased bilirubin                                 11              0                 0 Increased AST                                       79             <1                 0 Increased ALT                                       55             <1                 0 Haematologic
Decreased platelet count                            51              4                 2 Decreased haemoglobin                               31              1                 0 Decreased neutrophils                               24              1                 0 Potassium
Decreased potassium                                 26              2                 <1 
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 an online form
/https://sideeffects.health.gov.il