Adverse reactions : תופעות לוואי

6        ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling: 
•      Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers [see Warnings and Precautions (5.1)]
•      Central Nervous System Effects [see Warnings and Precautions (5.2)]
•      Hyperlipidemia [see Warnings and Precautions (5.3)]
•      Atrioventricular Block [see Warnings and Precautions (5.4)]
•      Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.5)]
•      Hypertension [see Warnings and Precautions (5.6)]
•      Hyperglycemia [see Warnings and Precautions (5.7)] 
6.1     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.

The pooled safety population described in the Warnings and Precautions section reflects exposure to LORVIQUA in 476 patients who received 100 mg LORVIQUA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORVIQUA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORVIQUA were edema (56%), peripheral neuropathy (44%),
weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent Grade 3-4 laboratory abnormalities in ≥ 20% of 476 patients who received LORVIQUA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).


Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)
The safety of LORVIQUA was evaluated in 149 patients with ALK-positive NSCLC in a randomized, open-label, active-controlled trial for the treatment of patients with ALK- positive, locally advanced or metastatic, NSCLC who had not received previous systemic treatment for advanced disease [see Clinical Studies (14)]. The median duration of exposure to LORVIQUA was 16.7 months (4 days to 34.3 months) and 76% received LORVIQUA for at least 12 months.

Serious adverse reactions occurred in 34% of patients treated with LORVIQUA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients treated with LORVIQUA and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%).

Permanent discontinuation of LORVIQUA due to adverse reactions occurred in 6.7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORVIQUA was cognitive effects (1.3%). Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORVIQUA. The most frequent adverse reactions that led to dose interruptions of LORVIQUA were hypertriglyceridemia (7%), edema (5%), pneumonia (4.7%) cognitive effects (4.0%), mood effects (4.0%), and hypercholesterolemia (3.4%). Adverse reactions leading to dose reductions occurred in 21% of patients treated with LORVIQUA. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%).

Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORVIQUA in Study B7461006.

Table 2        Adverse Reactions (≥10% for all NCI CTCAE Grades or ≥2% for Grades 3-4) in Patients Treated with LORVIQUA in Study B7461006*
Adverse Reaction                 LORVIQUA              Crizotinib
N=149                N=142
All     Grade 3 or   All      Grade 3 or
Grades          4     Grades          4
(%)         (%)      (%)          (%)
Psychiatric
Mood effectsa                         16           2        5            0 Nervous system
Peripheral neuropathyb                34           2       15           0.7 Cognitive effectsc                    21           2        6            0 Headache                              17           0       18           0.7 Dizziness                             11           0       14            0 d
Sleep effects                         11          1.3      10            0 Respiratory
Dyspnea                               20          2.7      16           2.1 Cough                                 16           0       18            0 Respiratory failure                   2.7          2        0            0 Vascular disorders
Adverse Reaction                         LORVIQUA                           Crizotinib N=149                            N=142
All    Grade 3 or                All      Grade 3 or
Grades       4                   Grades          4
(%)        (%)                   (%)          (%)
Hypertension                                    18         10                    2.1           0 Ocular
Vision disordere                                18               0               39              0.7 Gastrointestinal
Diarrhea                                        21              1.3              52              0.7 Nausea                                          15              0.7              52              2.1 Constipation                                    17               0               30              0.7 Vomiting                                        13              0.7              39              1.4 Musculoskeletal and connective tissue                                             19              0.7              11               0 Arthralgia                                      15              0.7               7               0 Myalgiaf                                        15              0.7              11               0 Back pain                                       17               0                8               0 Pain in extremity
General
Edemag                                          56               4               40              1.4 Weight gain                                     38              17               13              2.1 Fatigueh                                        19              1.3              32              2.8 Pyrexia                                         17              1.3              13              1.4 Chest pain                                      11              1.3              14              0.7 Infections
Upper respiratory tract infectioni              11              0.7             7.7              1.4 Pneumonia                                       7.4              2              8.5              3.5 Bronchitis                                      6.7              2              2.1               0 Skin
Rashj                                           11               0              8.5               0 * Adverse reactions were graded using NCI CTCAE version 4.03.
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
a
Mood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress).
b
Peripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy).
c
Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: confusional state, delirium, disorientation).
d
Sleep effects (including insomnia, nightmare, sleep disorder, somnambulism).
e
Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).
f
Myalgia (including musculoskeletal pain, myalgia).
g
Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).
h
Fatigue (including asthenia, fatigue).
i
Upper respiratory tract infection (including upper respiratory infection).
j
Rash (including dermatitis acneiform, maculopapular rash, rash).


Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6.7%) and psychotic effects (3.4%).

Table 3        Laboratory Abnormalities Worsening from Baseline in >20% of Patients in Study B7461006
Laboratory Abnormality             LORVIQUA                  Crizotinib N=149                   N=142
All      Grade 3        All       Grade 3
Grades       or 4      Grades         or 4
(%)         (%)         (%)          (%)
Chemistry
Hypertriglyceridemiaa,A             95          22          27            0 Hypercholesterolemiaa,A             91          19          12            0 a,A
Increased creatinine                81          0.7         99           2.1 Increased GGTa,A                    52           6          41            6 Increased ASTa,A                    48           2          75           3.5 Hyperglycemiaa,A                    48           7          27           2.1 Increased ALTa,A                    44          2.7         75           4.3 a,A
Increased CPK                       39           2          64            5 Hypoalbuminemiaa,A                  36          0.7         61            6 Increased lipase a,A
28           7          34            5
Increased alkaline phosphatasea,A   23           0          50           0.7 Hyperkalemiaa,A                     21          1.3         27           2.1 Increased amylaseb,A                20          1.4         32           1.4 Hematology
Anemiaa,A                           48           2          38           2.8 Activated PTTc,B                    25           0          14            0 a,A
Lymphopenia                         23          2.7         43            6 Thrombocytopeniaa,A                 23           0           7           0.7 * Grades using NCI CTCAE version 4.03.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time.
N=number of patients who had at least one on-study assessment for the parameter of interest.
a
N=149 (LORVIQUA).
A
N=141 (crizotinib).
b
N=148 (LORVIQUA).
B
N=135 (crizotinib).
c
N=138 (LORVIQUA).

Previously Treated ALK-Positive Metastatic NSCLC

The data described below reflect exposure to LORVIQUA in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORVIQUA 100 mg orally once daily in Study B7461001, a multi-cohort, non-comparative trial [see Clinical Studies (14)]. The median duration of exposure to LORVIQUA was 12.5 months (1 day to 35 months) and 52% received LORVIQUA for ≥12 months. Patient characteristics were: median age of 53 years (19 to 85 years), age ≥65 years (18%), female (58%), White (49%), Asian (37%), and ECOG performance status 0 or 1 (96%).

The most frequent (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Of the worsening laboratory values occurring in ≥20% of patients, the most frequent were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.

Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). Permanent discontinuation of LORVIQUA for adverse reactions occurred in 8% of patients.

The most frequent adverse reactions that led to permanent discontinuation were respiratory failure (1.4%), dyspnea (0.7%), myocardial infarction (0.7%), cognitive effects (0.7%) and mood effects (0.7%). Approximately 48% of patients required dose interruption. The most frequent adverse reactions that led to dose interruptions were edema (7%), hypertriglyceridemia (6%), peripheral neuropathy (5%), cognitive effects (4.4%), increased lipase (3.7%), hypercholesterolemia (3.4%), mood effects (3.1%), dyspnea (2.7%), pneumonia (2.7%), and hypertension (2.0%). Approximately 24% of patients required at least 1 dose reduction for adverse reactions. The most frequent adverse reactions that led to dose reductions were edema (6%), peripheral neuropathy (4.7%), cognitive effects (4.1%), and mood effects (3.1%).

Tables 4 and 5 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORVIQUA in Study B7461001.

Table 4    Adverse Reactions Occurring in ≥10% of Patients in Study B7461001* LORVIQUA
(N=295)
Adverse Reaction
All Grades                Grade 3 or 4
(%)                       (%)
Psychiatric
Mood effectsa                              23                        1.7 Nervous system
Peripheral neuropathyb                     47                        2.7 c
Cognitive effects                          27                         2 Headache                                   18                        0.7 Dizziness                                  16                        0.7 d
Speech effects                             12                        0.3 Sleep effectse                             10                         0 Respiratory
Dyspnea                                     27                         5 Cough                                       18                         0 Ocular
Vision disorderf                           15                        0.3 Gastrointestinal
Diarrhea                                   22                        0.7 Nausea                                     18                        0.7 Constipation                               15                         0 Vomiting                                   12                         1 Table 4      Adverse Reactions Occurring in ≥10% of Patients in Study B7461001* LORVIQUA
(N=295)
Adverse Reaction
All Grades                Grade 3 or 4
(%)                       (%)
Musculoskeletal and connective tissue                                         23                        0.7 Arthralgia                                  17                         0 Myalgiag                                    13                        0.7 Back pain                                   13                        0.3 Pain in extremity
General
Edemah                                      57                        3.1 i
Fatigue                                     26                        0.3 Weight gain                                 24                        4.4 Pyrexia                                     12                        0.7 Infections
Upper respiratory tract infectionj           12                         0 Skin
Rashk                                        14                        0.3 * Adverse reactions were graded using NCI CTCAE version 4.03.
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
a
Mood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation).
b
Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance).
c
Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder).
d
Speech effects (including aphasia, dysarthria, slow speech, speech disorder) e
Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) f
Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).
g
Myalgia (including musculoskeletal pain, myalgia).
h
Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).
i
Fatigue (including asthenia, fatigue).
j
Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection).
k
Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%).


Table 5    Worsening Laboratory Values Occurring in ≥20% of Patients in Study B7461001*
LORVIQUA
Laboratory Abnormality            All Grades                 Grade 3 or 4 (%)                        (%)
Chemistry
Hypercholesterolemiaa                96                         18 a
Hypertriglyceridemia                 90                         18
Hyperglycemiab                       52                          5 a
Increased AST                        37                         2.1
Hypoalbuminemiac                     33                          1 a
Increased ALT                        28                         2.1
Increased lipased                    24                         10
Increased alkaline                   24                          1 phosphatasea                         22                         3.9
Increased amylasee                   21                         4.8 a
Hypophosphatemia                     21                          1
Hyperkalemiab                        21                          0 a
Hypomagnesemia
Hematology
Anemiab                              52                         4.8
Thrombocytopeniab                    23                         0.3 a
Lymphopenia                          22                         3.4
* Grades using NCI CTCAE version 4.03.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
N=number of patients who had at least one on-study assessment for the parameter of interest.
a
N=292.
b
N=293.
c
N=291.
d
N=290.
e
N=284.

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