Adverse reactions : תופעות לוואי

7     ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the prescribing information:
•     Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (6.1)] •     Hypertension [see Warnings and Precautions (6.2)]
•     Bradycardia [see Warnings and Precautions (6.3)]
•     Visual Disturbance [see Warnings and Precautions (6.4)]
•     Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (6.5)] •     Pancreatic Enzymes Elevation [see Warnings and Precautions (6.6)] •     Hepatotoxicity [see Warnings and Precautions (6.7)]
•     Hyperglycemia [see Warnings and Precautions (6.8)]
•     Photosensitivity [see Warnings and Precautions (6.9)]

7.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Advanced ALK-positive NSCLC Without Prior ALK-targeted Therapy
In ALTA 1L, the safety of ALUNBRIG was evaluated in 136 patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy [see Clinical Studies (13)]. The median duration of treatment with ALUNBRIG when administered as 90 mg orally once daily for the first 7 days; then increased to 180 mg orally once daily, was 24.3 months. A total of 106 (78%) patients were exposed to ALUNBRIG for greater than or equal to 6 months including 92 (68%) patients exposed for greater than or equal to 1 year. The median relative dose intensity was 97% for ALUNBRIG.
The study population (N = 275) characteristics were: median age 59 years (range: 27 to 89), age less than 65 years (68%), female (55%), White (59%), Asian (39%), Stage IV disease (93%), NSCLC adenocarcinoma histology (96%), never smoker (58%), ECOG Performance Status (PS) 0 or 1 (95%), and CNS metastases at baseline (30%) [see Clinical Studies (13)].
Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions were pneumonia (4.4%), ILD/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (2.2%). Fatal adverse reactions occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).
In ALTA 1L, 13% of patients receiving ALUNBRIG permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (3.7%) and pneumonia (2.2%). In ALTA 1L, 38% of patients required a dose reduction due to adverse reactions.
The most common adverse reaction that led to dose reduction was increased creatine phosphokinase (15%), increased lipase (6.6%), increased amylase (4.4%), increased aspartate aminotransferase (2.2%), ILD/pneumonitis (2.2%) and hypertension (2.2%).
Table 3 and Table 4 summarize the common adverse reactions and laboratory abnormalities observed in ALTA 1L.




Table 3: Adverse Reactions in ≥10% (All Grades*) or ≥2% (Grades 3-4) of Patients by Arm in ALTA 1L (N = 273)
ALUNBRIG                     Crizotinib
N = 136                      N = 137
All Grades     Grades 3-4    All Grades     Grades 3-4
Adverse Reactions                    (%)           (%)            (%)            (%) Gastrointestinal Disorders
Diarrhea                                     53            2.2           57             2.9 Nausea                                       30            2.2           58             2.9 Abdominal pain†                              24            0.7           33             3.6 Vomiting                                     21            0.7           44             2.2 Constipation                                 18             0            42              0 Stomatitis‡                                  13            0.7           8.8             0 Dyspepsia                                     8             0            16             0.7 Gastroesophageal reflux disease              0.7            0            11              0 Skin and Subcutaneous Tissue
Disorders
Rash§                                        40            2.9           17              0 Pruritus¶                                    20            0.7           5.8            0.7 Respiratory, Thoracic and Mediastinal
Disorders
Cough                                        35             0             20             0 Dyspnea#                                     25            2.9           22Ɖ            3.6 ILD/Pneumonitis                              5.1           2.9           2.2            0.7 Pulmonary embolism                           2.2           2.2           5.8Ɖ           2.9 Vascular Disorders
HypertensionÞ                                32             13            8             2.9 General Disorders and Administration
Site Conditions
Fatigueβ                                     32            1.5            40            2.2 Edemaà                                       18            0.7            48            0.7 Pyrexia                                      15            0.7            15             0 Musculoskeletal and Connective Tissue
Disorders
Myalgiaẻ                                     28             0             23             0 Back pain                                    21            0.7            17            1.5 Arthralgia                                   14             0             12             0 Pain in extremity                            5.1            0             15            0.7 Nervous System Disorders
Headacheð                                    22            2.2            17             0 Dizziness                                    15            0.7            20            0.7 Peripheral neuropathyø                       11            0.7            18             0 Dysgeusia                                    2.9            0             14             0 Investigations
Increased Blood cholesterolý                 13             0            0.7             0 Cardiac Disorders
Bradycardia£                                 12            0.7            23             0 Infections and Infestations
Pneumonia¥                                   15Ɖ           5.1           6.6Ɖ           2.9 Upper respiratory tract infectionOE          12             0             10             0 
Nasopharyngitis                                     8               0              11                0 Urinary tract infection                            5.9             0.7             8.8              2.2 Metabolism and Nutrition Disorders
Decreased Appetite                                 8.8             0.7              19              2.9 Eye Disorders
Visual Disturbanceoe                               7.4              0               53              0.7 

* Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 †  Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort
‡ Includes aphthous ulcer, mouth ulceration, oral mucosal blistering and stomatitis 
§ Includes dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis contact, drug eruption, erythema,  palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption, urticaria ¶ Included pruritus, allergic pruritus, and generalized pruritus

# Include dyspnea and exertional dyspnea

Þ Includes hypertension and systolic hypertension
â Includes asthenia and fatigue

à Includes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral  edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face ẻ Includes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia 
ð
Includes headache and migraine
ø
Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy
ý
Includes blood cholesterol increased, hypercholesterolaemia
£
Includes bradycardia, heart rate decreased, sinus bradycardia
¥
Includes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia
OE
Includes upper respiratory tract infection and viral upper respiratory tract infection oe
Includes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters Ɖ
Includes Grade 5 events




Table 4: Laboratory Abnormalities in ≥20% (All Grades*) of Patients by Arm in ALTA 1L (N = 273) ALUNBRIG                              Crizotinib
N = 136**                            N = 137**
All Grades          Grades 3-4        All Grades      Grades 3-4
Laboratory Abnormality                  (%)                (%)                (%)            (%) Chemistry
Increased creatine phosphokinase             81                 24                68                 4.8 Increased aspartate                          72                 4.5               70                 5.2 aminotransferase
Increased lipase                             59                 17                36                 9.8 Hyperglycemia†                               56                 7.5               37                 3.7 Increased alanine aminotransferase           52                 5.2               77                 13 Increased amylase                            52                 6.8               25                  3 Decreased phosphorous                        41                 3.7               39                  6 Increased alkaline phosphatase               36                  3                49                 1.5 Increased creatinine                         25                  0                33                  0 Potassium increased                          24                 1.5               31                 3.7 Increased calcium                            22                  0                1.5                 0 Decreased magnesium                          21                  0                6.9                 0 Decreased albumin                            15                 0.8               52                 3.7 Decreased calcium                            15                  0                67                 1.5 Hematology
Hemoglobin decreased                         41                 2.3               36                 1.5 Lymphocyte count decreased                   42                 9.3               30                 5.4 Neutrophil count decreased                   12                  0                34                 6.8 
* Per CTCAE version 4.03
** Denominator for each laboratory parameter may vary and is defined as the number of patients who had both, baseline and post-baseline test
† Elevated blood insulin was also observed in both arms

Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (3.7%).

ALK-positive Advanced or Metastatic NSCLC Previously Treated with Crizotinib The safety of ALUNBRIG was evaluated in 219 patients with locally advanced or metastatic ALK-positive NSCLC who received at least 1 dose of ALUNBRIG in ALTA after experiencing disease progression on crizotinib. Patients received ALUNBRIG 90 mg once daily continuously (90 mg group) or 90 mg once daily for 7 days followed by 180 mg once daily (90→180 mg group). The median duration of treatment was 7.5 months in the 90 mg group and 7.8 months in the 90→180 mg group. A total of 150 (68%) patients were exposed to ALUNBRIG for greater than or equal to 6 months and 42 (19%) patients were exposed for greater than or equal to 1 year.

The study population (N=222) characteristics were: median age 54 years (range: 18 to 82), age less than 65 years (77%), female (57%), White (67%), Asian (31%), Stage IV disease (98%), NSCLC adenocarcinoma histology (97%), never or former smoker (95%), ECOG Performance Status (PS) 0 or 1 (93%), and CNS metastases at baseline (69%) [see Clinical Studies (13)].


Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

In ALTA, 2.8% of patients in the 90 mg group and 8.2% of patients in the 90→180 mg group permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90 mg group and 1.8% in the 90→180 mg group) and pneumonia (1.8% in the 90→180 mg group only).

In ALTA, 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90 mg group and 20% in the 90→180 mg group). The most common adverse reaction that led to dose reduction was increased creatine phosphokinase for both regimens (1.8% in the 90 mg group and 4.5% in the 90→180 mg group).

Table 5 and Table 6 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.

Table 5: Adverse Reactions in ≥ 10% (All Grades*) or ≥ 2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)
90 mg once                    90→180 mg once daily N = 109                   daily N = 110
Adverse Reactions                 All Grades    Grades 3-        All            Grades 3- (%)           4 (%)             Grades        4 (%)
Gastrointestinal Disorders
Nausea                                           33              0.9            40              0.9 Diarrhea                                         19               0             38               0 Vomiting                                         24              1.8            23               0 Constipation                                     19              0.9            15               0 Abdominal Pain†                                  17               0             10               0 
General Disorders and Administration Site Conditions
Fatigue‡                                      29                 1.8            36               0 Pyrexia                                       14                  0             6.4             0.9 Respiratory, Thoracic and Mediastinal Disorders
Cough                                         18                  0             34               0 Dyspnea§                                      27                 2.8            21             1.8‡‡ ILD/Pneumonitis                               3.7                1.8            9.1             2.7 Hypoxia                                       0.9                 0             2.7             2.7 Nervous System Disorders
Headache¶                                        28               0             27              0.9 Peripheral Neuropathy#                        13                 0.9            13              1.8 Skin and Subcutaneous Tissue Disorders
RashÞ                                         15                 1.8            24              3.6 Vascular Disorders
Hypertension                                  11                 5.5            21              6.4 Musculoskeletal and Connective Tissue Disorders
Muscle Spasms                                 12                  0             17               0 Back pain                                     10                 1.8            15              1.8 

Myalgia**                                             9.2              0              15               0.9 Arthralgia                                            14              0.9             14                0 Pain in extremity                                     11               0              3.6              0.9 Metabolism and Nutrition Disorders
Decreased Appetite                                    22              0.9             15               0.9 Eye Disorders
Visual Disturbance††                                  7.3             0               10               0.9 Infections
Pneumonia                                            4.6           2.8‡‡             10              5.5‡‡ Psychiatric Disorders
Insomnia                                              11              0               7.3               0 
*Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 †Includes abdominal distension, abdominal pain, and epigastric discomfort ‡Includes asthenia and fatigue
§Includes dyspnea and exertional dyspnea
¶Includes headache and sinus headache
#includes peripheral sensory neuropathy and paresthesia
ÞIncludes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash **Includes musculoskeletal pain and myalgia
††Includes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment
‡‡Includes one Grade 5 event


Table 6: Laboratory Abnormalities in ≥20% (All Grades*) of Patients by Regimen in ALTA (N=219) 90 mg once                           90→180 mg once daily N= 109                          daily N=110
Laboratory Abnormality
All Grades        Grades 3-4             All            Grades 3-
(%)               (%)                   Grades         4 (%)
(%)
Chemistry
Increased aspartate aminotransferase             38                   0.9                   65               0 Hyperglycemia†                                   38                   3.7                   49              3.6 Increased creatine phosphokinase                 27                   2.8                   48              12 Increased lipase                                 21                   4.6                   45              5.5 Increased alanine aminotransferase               34                    0                    40              2.7 Increased amylase                                27                   3.7                   39              2.7 Increased alkaline phosphatase                   15                   0.9                   29              0.9 Decreased phosphorous                            15                   1.8                   23              3.6 Prolonged activated partial                      22                   1.8                   20              0.9 thromboplastin time
Hematology
Anemia                                           23                   0.9                   40              0.9 Lymphopenia                                      19                   2.8                   27              4.5 
*Per CTCAE version 4.0
†Elevated blood insulin was observed in both regimens

Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (0.9%).


Other Adverse Reactions from Multiple Clinical Trials
In a pooled clinical trial population consisting of three studies with 274 patients treated with ALUNBRIG at the recommended dose, the following adverse reactions and laboratory abnormalities were reported: white blood cell count decreased (28%), hyponatremia (20%), hypokalemia (19%), decreased platelet count (10%), dry skin (4.7%), pain (3.3%), and musculoskeletal stiffness (1.1%).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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