Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of safety profile
The safety data of elotuzumab have been assessed from a total of 682 patients with multiple myeloma treated with elotuzumab in combination with lenalidomide and dexamethasone (451 patients), bortezomib and dexamethasone (103 patients) or pomalidomide and dexamethasone (128 patients) pooled across 8 clinical trials. The majority of adverse reactions were mild to moderate (Grade 1 or 2).

The most serious adverse reaction that may occur during elotuzumab treatment is pneumonia.

The most common adverse reactions (occurring in > 10% of patients) with elotuzumab treatment were IRRs, diarrhoea, herpes zoster, nasopharyngitis, cough, pneumonia, upper respiratory tract infection, lymphopenia and weight decreased.

Tabulated list of adverse reactions
Adverse reactions reported in 682 patients with multiple myeloma who were treated with elotuzumab in 8 clinical trials are presented in Table 5.

These reactions are presented by system organ class and by frequency. Frequencies 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 available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.



Table 5:      Adverse reactions in patients with multiple myeloma treated with Empliciti System Organ Class         Adverse reactions          Frequency overall      Grade 3/4 frequency a
Infections and             Pneumonia                  Very common            Common infestations               Herpes zosterb             Common                 Uncommon 
Upper respiratory tract           Very common                    Common infection
Nasopharyngitis                   Very common                    Not known Blood and lymphatic            Lymphopeniac                      Very common                    Common system disorders
Leukopenia                        Common                         Common Immune system                  Anaphylactic reaction             Uncommon                       Uncommon disorders                      Hypersensitivity                  Common                         Uncommon Psychiatric disorders          Mood altered                      Common                         Not known Nervous system                 Headache                          Very common                    Uncommon disorders                      Hypoaesthesia                     Common                         Uncommon Vascular disorders             Deep vein thrombosis              Common                         Common Respiratory, thoracic          Coughd                            Very common                    Uncommon and mediastinal                Oropharyngeal pain                Common                         Not known disorders
Gastrointestinal               Diarrhoea                         Very common                    Common disorders
Skin and subcutaneous          Night sweats                      Common                         Not known tissue disorders
General disorders and          Chest pain                        Common                         Common administration site            Fatigue                           Very common                    Common conditions                     Pyrexia                           Very common                    Common Investigations                 Weight decreased                  Very common                    Uncommon Injury, poisoning and          Infusion related                  Common                         Uncommon procedural                     reaction complications a
The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia.
b
The term herpes zoster is a grouping of the following terms: herpes zoster, oral herpes, and herpes virus infection.
c
The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased.
d
The term cough includes the following terms: cough, productive cough, and upper airway cough syndrome.

Exposure-adjusted rates for adverse reactions (all Grades and Grade 3/4) in CA204004, a clinical trial in patients with multiple myeloma comparing Empliciti combined with lenalidomide and dexamethasone treatment (N = 318) to lenalidomide and dexamethasone treatment (N = 317), is shown in Table 6.



Table 6:    CA204004 Exposure-adjusted rates for adverse reactions for Empliciti-treated patients versus lenalidomide and dexamethasone-treated patients [includes multiple occurrences in all treated patients]
Empliciti +                               Lenalidomide and Dexamethasone Lenalidomide and Dexamethasone
N = 318                                               N = 317
All grades               Grade 3/4                 All grades                Grade 3/4 Adverse             Event     Rate           Event      Rate           Event      Rate            Event      Rate reaction            count     (incidence     count      (incidence     count      (incidence      count      (incidence rate/100                  rate/100                  rate/100                   rate/100 patient                   patient                   patient                    patient years)                    years)                    years)                     years) Diarrhoea           303       59.2           19         3.7            206        49.3            13         3.1 Pyrexia             220       43.0           8          1.6            116        27.7            10         2.4 Fatigue             205       40.0           33         6.4            145        34.7            26         6.2 a
Cough               170       33.2           1          0.2            85         20.3            -          - Nasopharyngitis     151       29.5           -          -              116        27.7            -          - Upper               129       25.2           2          0.4            95         22.7            4          1.0 respiratory tract infection
Lymphopeniab        90        17.6           65         12.7           57         13.6            31         7.4 Headache            88        17.2           1          0.2            40         9.6             1          0.2 Pneumoniac          80        15.6           54         10.5           54         12.9            34         8.1 Leukopenia          70        13.7           19         3.7            65         15.5            21         5.0 Herpes zosterd      51        10.0           5          1.0            24         5.7             3          0.7 Oropharyngeal       45        8.8            -          -              17         4.1             -          - pain
Weight              44        8.6            4          0.8            20         4.8             -          - decreased
Night sweats        31        6.1            -          -              12         2.9             -          - Chest pain          29        5.7            2          0.4            12         2.9             1          0.2 Deep vein           26        5.1            18         3.5            12         2.9             7          1.7 thrombosis
Hypoaesthesia       25        4.9            1          0.2            12         2.9             -          - Mood altered        23        4.5            -          -              8          1.9             -          - Hypersensitivity    10        2.0            -          -              4          1.0             1          0.2 a
The term cough includes the following terms: cough, productive cough, and upper airway cough syndrome.
b
The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased.
c
The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia.
d
The term herpes zoster is a grouping of the following terms: herpes zoster, oral herpes, and herpes virus infection.

Exposure-adjusted rates for adverse reactions (all Grades and Grade 3/4) in CA204125, a clinical trial in patients with multiple myeloma comparing Empliciti combined with pomalidomide and dexamethasone treatment (N = 60) to pomalidomide and dexamethasone treatment (N = 55), is shown in Table 7.


Table 7:    CA204125 Exposure-adjusted rates for adverse reactions for Empliciti-treated patients versus pomalidomide and dexamethasone-treated patients [includes multiple occurrences in all treated patients]
Empliciti +                             Pomalidomide and Dexamethasone Pomalidomide and Dexamethasone
N = 60                                                N = 55
All grades              Grade 3/4                 All grades                Grade 3/4 Adverse             Event     Rate          Event       Rate           Event      Rate           Event      Rate reaction            count     (incidence    count       (incidence     count      (incidence     count      (incidence rate/100                  rate/100                  rate/100                  rate/100 patient                   patient                   patient                   patient years)                    years)                    years)                    years) Cougha              12        25.2          1           2.1           9           26.2           -          - Nasopharyngitis     12        25.2          -           -             10          29.1           -          - Upper               9         18.9          -           -             10          29.1           1          2.9 respiratory tract infection
Leukopenia          13        27.3          9           18.9          3           8.7            2          5.8 Lymphopeniab        10        21.0          6           12.6          1           2.9            1          2.9 Pneumoniac          6         12.6          4           8.4           9           26.2           8          23.3 Herpes zosterd      5         10.5          -           -             3           8.7            -          - Infusion related    2         4.2           1           2.1           1           2.9            -          - reaction
Chest pain          2         4.2           -           -             1           2.9            -          - Night sweats        1         2.1           -           -             -           0.0            -          - Hypoaesthesia       1         2.1           -           -             1           2.9            -          - Mood altered        1         2.1           -           -             1           2.9            -          - a
The term cough includes the following terms: cough, productive cough, and upper airway cough syndrome.
b
The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased.
c
The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia.
d
The term herpes zoster is a grouping of the following terms: herpes zoster, oral herpes, herpes virus infection and ophthalmic herpes zoster.

Description of selected adverse reactions

IRRs
In the clinical trials of patients with multiple myeloma IRRs were reported in approximately 10% of premedicated patients treated with Empliciti combined with lenalidomide and dexamethasone (N = 318) and 3% of premedicated patients treated with Empliciti combined with pomalidomide and dexamethasone (N=60) (see section 4.4). The rate of mild to moderate IRRs was > 50% in patients who were not premedicated. All reports of IRR were ≤ Grade 3. Grade 3 IRRs occurred in 1% of patients. In study CA204004, the most common symptoms of an IRR included fever, chills, and hypertension. Five percent (5%) of patients required interruption of the administration of Empliciti for a median of 25 minutes due to IRR, and 1% of patients discontinued due to IRRs. Of the patients who experienced an IRR, 70% (23/33) had the reaction during the first dose. In study CA204125, all of the reported IRRs occurred during the first treatment cycle and were ≤ Grade 2.

Infections
The incidence of infections, including pneumonia, was higher with Empliciti treatment than with control (see section 4.4). In a clinical trial of patients with multiple myeloma (CA204004), infections were reported in 81.4% of patients in the Empliciti combined with lenalidomide and dexamethasone 

arm (N = 318) and 74.4% in lenalidomide and dexamethasone arm (N = 317). Grade 3-4 infections were noted in 28% and 24.3% of Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone treated patients, respectively. Fatal infections were infrequent and were reported in 2.5% of Empliciti combined with lenalidomide and dexamethasone and 2.2% of lenalidomide and dexamethasone treated patients. The incidence of pneumonia was higher in the Empliciti combined with lenalidomide and dexamethasone arm compared to lenalidomide and dexamethasone arm reported at 15.1% vs. 11.7% with a fatal outcome at 0.6% vs. 0%, respectively.

In a clinical trial of patients with multiple myeloma (CA204125), infections were reported in 65% of patients in the Empliciti combined with pomalidomide and dexamethasone arm (N = 60) and 65.5% in the pomalidomide and dexamethasone arm (N = 55). Grade 3-4 infections were noted in 13.3% and 21.8% of Empliciti combined with pomalidomide and dexamethasone and pomalidomide and dexamethasone treated patients, respectively. Fatal infections (i.e. Grade 5 infections) were reported in 5% of Empliciti combined with pomalidomide and dexamethasone and 3.6% of pomalidomide and dexamethasone treated patients.

SPMs
The incidence of SPMs was higher with Empliciti treatment than with control (see section 4.4). In the clinical trial of patients with multiple myeloma (CA204004), invasive SPMs have been observed in 6.9% of patients treated with Empliciti combined with lenalidomide and dexamethasone (N = 318) and 4.1% of patients treated with lenalidomide and dexamethasone (N = 317). SPMs are known to be associated with lenalidomide exposure which was extended in patients treated with Empliciti combined with lenalidomide and dexamethasone vs. lenalidomide and dexamethasone. The rate of haematologic malignancies were the same between the two treatment arms (1.6%). Solid tumours were reported in 2.5% and 1.9% of Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone treated patients, respectively. Non-melanoma skin cancer was reported in 3.1% and 1.6% of patients treated with Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone, respectively.

There were no SPM events reported in patients treated in the Empliciti combined with pomalidomide and dexamethasone study arm (N = 60) and 1 (1.8%) in patients treated in the pomalidomide and dexamethasone arm (N = 55) in study CA204125.

Deep vein thrombosis
In a clinical trial of patients with multiple myeloma (CA204004), deep vein thromboses were reported in 7.2% of patients treated with Empliciti combined with lenalidomide and dexamethasone (N = 318) and 3.8% of patients treated with lenalidomide and dexamethasone (N = 317). Among patients treated with aspirin, deep vein thromboses were reported in 4.1% of patients treated with Empliciti combined with lenalidomide and dexamethasone (E-Ld) and 1.4% of patients treated with lenalidomide and dexamethasone (Ld). The rates of deep vein thromboses observed between treatment arms were similar for patients given prophylaxis with low molecular weight heparin (2.2% in both treatment arms), and for patients given vitamin K antagonists the rates were 0% for patients treated with E-Ld and 6.7% for patients treated with Ld.

Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity to Empliciti.
Of 390 patients across four clinical trials who were treated with Empliciti and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in 19 of 299 patients in CA204004. In the majority of patients, immunogenicity occurred early in treatment and was transient resolving by 2 to 4 months. There was no clear causal evidence of altered pharmacokinetic, efficacy, or toxicity profiles with anti-product antibody development based on the population pharmacokinetic and exposure-response analyses.

Of the 53 patients in CA204125 treated with Empliciti and evaluable for the presence of anti-product antibodies, 19 patients (36%) tested positive, of whom 1 patient tested persistent positive, for treatment-emergent anti-product antibodies by an ECL assay. In these 19 patients, anti-product 
antibodies occurred within the first 2 months of the initiation of Empliciti treatment. Anti-product antibodies resolved by 2 to 3 months in 18 (95%) of these 19 patients. Neutralizing antibodies were detected in 2 of 53 patients.

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/