Special Warning : אזהרת שימוש

5         WARNINGS AND PRECAUTIONS
5.1       Gastrointestinal Adverse Reactions
Severe gastrointestinal adverse reactions occurred in patients treated with ZYKADIA 750 mg under fasted conditions (see Adverse Reactions 6.1). Diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of 925 patients, including severe cases (Grade 3 or 4) in 14% of patients treated with ZYKADIA across clinical studies. Diarrhea, nausea, vomiting, or abdominal pain leading to dose interruptions or reductions occurred in 36% of patients and leading to treatment discontinuation occurred in 1.6% of patients.
The incidence and severity of gastrointestinal adverse reactions were reduced for patients treated with ZYKADIA 450 mg with food in a dose optimization study (ASCEND-8). Diarrhea, nausea, vomiting, or abdominal pain occurred in 79% of 108 patients treated with ZYKADIA at the recommended dose of 450 mg with food. Of these, 53% were Grade 1 events and 24% were Grade 2 events. One patient (0.9%) experienced Grade 3 diarrhea, and one patient (0.9%) experienced Grade 3 vomiting. One patient (0.9%) required dose ZYK SPI 20FEB22 CL V5                                                                                     USPI October 2021 adjustment due to vomiting. Eleven (10%) patients had diarrhea, nausea, vomiting, or abdominal pain that required at least one dose interruption.
Monitor and manage patients using standard of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold ZYKADIA if gastrointestinal adverse reaction is severe or intolerable and is not responsive to antiemetics or antidiarrheals. Upon improvement, resume ZYKADIA at a reduced dose [see  Dosage and Administration (2.3)].
5.2     Hepatotoxicity
Drug-induced hepatotoxicity occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Elevations in alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) occurred in 28% and elevations in aspartate aminotransferase (AST) >5 times ULN occurred in 16% of 925 patients across clinical studies.
Concurrent elevations in ALT >3 times the ULN and total bilirubin >2 times the ULN, with alkaline phosphatase <2 times the ULN occurred in 0.3% of patients across clinical studies. Approximately 1% of patients required permanent discontinuation due to hepatotoxicity.
Monitor with liver laboratory tests, including ALT, AST, and total bilirubin, once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIA [see Dosage and Administration (2.3) ].
5.3     Interstitial Lung Disease /Pneumonitis
Severe, life-threatening, or fatal interstitial lung diseases (ILD)/pneumonitis occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, ILD/pneumonitis was reported in 2.4% of 925 patients treated with ZYKADIA. Grade 3 or 4 ILD/pneumonitis was reported in 1.3% of patients, with fatal events reported in 0.2% of patients. Ten patients (1.1%) discontinued ZYKADIA across clinical studies due to ILD/pneumonitis.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis [see Dosage and Administration (2.3)].
5.4     QT Interval Prolongation
QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmia (e.g., torsades de pointes) or sudden death, occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, 6% of 919 patients with at least one post-baseline electrocardiogram (ECG) assessment had an increase from baseline of QTc >60 msec. Approximately 1.3% of patients taking ZYKADIA 750 mg under fasted conditions were found to have a QTc >500 msec. ZYKADIA causes concentration-dependent increases in the QTc interval [see Clinical Pharmacology (12.2)]. Across clinical studies, 0.2% of patients discontinued ZYKADIA due to QTc prolongation.
When possible, avoid use of ZYKADIA in patients with congenital long QT syndrome. Conduct periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Based on the severity of the adverse reaction, withhold ZYKADIA, with resumption at a reduced dose, or permanently discontinue ZYKADIA [see Dosage and Administration (2.3)].
5.5     Hyperglycemia
Hyperglycemia occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, Grade 3 or 4 hyperglycemia, based on laboratory values, occurred in 13% of 925 patients.
Monitor fasting serum glucose prior to the start of ZYKADIA treatment and periodically thereafter as clinically ZYK SPI 20FEB22 CL V5                                                                             USPI October 2021 indicated. Initiate or optimize anti hyperglycemic medications as indicated. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIA [see  Dosage and Administration (2.3)].
5.6     Bradycardia
Bradycardia occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, sinus bradycardia, defined as a heart rate < 50 beats per minute, was noted as a new finding in 1.1% of 925 patients.
Bradycardia was reported as an adverse reaction in 1% of patients. No patient required discontinuation and 0.1% required interruption with subsequent dose reduction for bradycardia.
Avoid using ZYKADIA in combination with other products known to cause bradycardia (e.g., beta-blockers, non- dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose upon resolution of bradycardia, or permanently discontinue ZYKADIA [see  Dosage and Administration (2.3)].
5.7     Pancreatitis
Pancreatitis occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Pancreatitis, including one fatality, occurred in less than 1% of patients receiving ZYKADIA in clinical studies. Grade 3 or 4 elevations of amylase occurred in 7% of patients receiving ZYKADIA across clinical studies, while Grade 3 or 4 elevations of lipase occurred in 14% of patients.
Monitor lipase and amylase prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Based on the severity of the laboratory abnormalities, withhold ZYKADIA with resumption at a reduced dose [see Dosage and Administration (2.3)].
5.8     Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, ZYKADIA can cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for 6 months following completion of therapy.
Based on the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].


6       ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2)]
• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] • QT Interval Prolongation [see Warnings and Precautions (5.4) ]
• Hyperglycemia [see Warnings and Precautions (5.5)]
• Bradycardia [see Warnings and Precautions (5.6)]

ZYK SPI 20FEB22 CL V5                                                                              USPI October 2021 •     Pancreatitis [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 data in the Warnings and Precautions section reflect exposure to ZYKADIA 750 mg once daily under fasted conditions in 925 patients with ALK-positive NSCLC across seven clinical studies, including ASCEND-4 and ASCEND-1, described below, a randomized active-controlled study, two single arm studies, and two dose- escalation studies. The majority of patients enrolled in these studies had received prior treatment with chemotherapy and/or crizotinib for NSCLC. Among these 925 patients, the most common adverse reactions (≥25% incidence) were diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and weight loss.
Approximately 45% of patients initiating treatment with ZYKADIA 750 mg under fasted conditions had an adverse reaction that required at least one dose reduction and 66% of patients had an adverse reaction that required at least one dose interruption. The median time to first dose reduction due to any reason was 7 weeks.
Dose Optimization Study: Dosing Regimen of 450 mg Daily with Food
In ASCEND-8, a dose optimization study, ZYKADIA 450 mg daily with food (N = 108) was compared to 750 mg daily under fasted conditions (N = 110) in both previously treated and untreated patients with ALK-positive NSCLC. The overall safety profile of ZYKADIA 450 mg with food was consistent with ZYKADIA 750 mg fasted, except for a reduction in gastrointestinal adverse reactions, while achieving comparable steady-state exposure [see Clinical Pharmacology (12.3)]. The most common adverse reactions (≥ 25% incidence) in the 450 mg with food arm were diarrhea, nausea, abdominal pain, vomiting, and fatigue. The incidence and severity of gastrointestinal adverse reactions (diarrhea 59%, nausea 43%, and vomiting 38%) were reduced for patients treated with ZYKADIA 450 mg with food; Grade ≥ 3 adverse reactions were reported in two patients (1.9%): Grade 3 diarrhea and Grade 3 vomiting in one patient each [see Warnings and Precautions (5.1)].
In patients treated with ZYKADIA 450 mg with food, 24% of patients had an adverse reaction that required at least one dose reduction and 56% of patients had an adverse reaction that required at least one dose interruption.
The median time to first dose reduction due to any reason was 8 weeks.


Previously Untreated ALK-Positive Metastatic NSCLC
The safety of ZYKADIA was evaluated in ASCEND-4, an open-label, randomized, active-controlled multicenter study of 376 previously untreated ALK-positive NSCLC patients [see Clinical Studies (14.1)]. Patients received ZYKADIA 750 mg daily (N=189) under fasted conditions or chemotherapy and maintenance chemotherapy (N=187). Chemotherapy regimens were pemetrexed (500 mg/m2) and investigator’s choice of cisplatin (75 mg/m2) or carboplatin [area under the curve (AUC) of 5 - 6 mg*min/mL] administered every 21 days. Patients who completed 4 cycles of chemotherapy without progressive disease received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days. The median duration of exposure to ZYKADIA was 18 months.
The demographic characteristics of the study population were 57% female, median age 54 years (range: 22 to 81 years); 22% age 65 years or older, 54% white, 42% Asian, 2% black, and 2% other races. Patients were enrolled in Europe (53%), Asia Pacific (42%), and South America (5%) regions. The majority of patients had adenocarcinoma (97%), never smoked (61%) and 32% had brain metastases at screening.
The following fatal adverse reactions occurred in 4 patients treated with ZYKADIA: Myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause.


ZYK SPI 20FEB22 CL V5                                                                                USPI October 2021 Serious adverse reactions were reported in 38% of patients treated with ZYKADIA. The most frequent serious adverse reactions were pneumonia (4%), pleural effusion (4%), vomiting (4%), nausea (3%), dyspnea (3%), hyperglycemia (3%), AST increased (2%), lung infection (2%), and pericardial effusion (2%).
Among patients treated with ZYKADIA, dose interruptions due to adverse reactions occurred in 77%, dose reductions were required in 66%, and adverse reactions that led to discontinuation of therapy occurred in 12% of patients. The most frequent adverse reactions, reported in at least 10% of patients treated with ZYKADIA, that led to dose interruptions or reductions were: Increased ALT (48%), increased AST (34%), vomiting (15%), increased blood creatinine (14%), increased gamma-glutamyl transpeptidase (GGT) (13%), diarrhea (13%), and nausea (13%). The most frequent adverse reactions that led to discontinuation of ZYKADIA in 1% or more of patients in ASCEND-4 were increased blood creatinine (2.1%), increased amylase (1.1%), and increased lipase (1.1%).
Tables 3 and 4 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-4.
Table 3: Adverse Reactions (>10% for All Grades* or ≥2% for Grades 3-4) of Patients in ASCEND-4 ZYKADIA                           Chemotherapy
N=189                              N=175a
All Grades       Grade 3-4          All Grades       Grade 3-4
%               %                   %               %
Gastrointestinal**
Diarrhea                                             85               4.8               11               1.1 Nausea                                               69               2.6               55                5 Vomiting                                             67                5                36                6 Abdominal painb                                      40               3.7               13                0 Constipation                                         20                0                22                0 Esophageal disorderc                                 15               0.5               8                0.6 General
Fatigued                                             45                7                49                6 Non-cardiac chest pain                               21               1.1               10               0.6 Back pain                                            19               1.6               18               2.3 Pyrexia                                             19                0                14               1.1 Pain in extremity                                   13                0                 7                0 Musculoskeletal pain                                11               0.5                6               0.6 


ZYK SPI 20FEB22 CL V5                                                                              USPI October 2021 ZYKADIA                                 Chemotherapy
N=189                                   N=175a
All Grades       Grade 3-4               All Grades       Grade 3-4
%               %                        %               %
Pruritus                                                 11              0.5                       5              0 Metabolism and Nutrition
Decreased appetite                                        34                  1.1                 32                  1.1 Weight loss                                               24                  3.7                 15                  0.6 Respiratory
Cough                                                     25                   0                  17                   0 Neurologic
Headache                                                  19                  0.5                 13                  1.1 Dizziness                                                 12                  1.1                 10                  0.6 Skin
Rashe                                                     21                  1.1                  8                  0.6 Cardiac
Prolonged QT interval                                     12                  2.6                 1.1                 0.6 Pericarditisf                                             4.2                 1.6                 2.3                 1.1 *National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).
**For frequency of gastrointestinal adverse reactions at the recommended dose of 450 mg with food [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].
a
Twelve patients randomized to chemotherapy did not receive study drug.
b
Abdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, and epigastric discomfort) c
Esophageal disorder (dyspepsia, gastroesophageal reflux disease, and dysphagia) d
Fatigue (fatigue and asthenia) e
Rash (rash, dermatitis acneiform, rash maculo-papular) f
Pericarditis (pericardial effusion and pericarditis)
Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg under fasted conditions included: vision disorder (4%; comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, reduced visual acuity, or vitreous floaters), bradycardia (4%), ILD/pneumonitis (2%), hepatotoxicity (2%) and renal failure (2%). In addition, the adverse reaction of photosensitivity was reported in 1.1% of patients.



ZYK SPI 20FEB22 CL V5                                                                                          USPI October 2021 Table 4: Laboratory Abnormalities Occurring in >10% (All Grades*) of Patients in ASCEND-4 ZYKADIA                                Chemotherapy
N=189                                     N=175a
All Grades          Grade 3–4             All Grades        Grade 3–4 %                  %                      %                %
Chemistry
Increased ALT                                                 91                  34                    65                 3.4 Increased AST                                                 86                  21                    58                 2.3 Increased GGT                                                 84                  49                    67                 10 Increased alkaline phosphatase                                81                  12                    47                 1.7 Increased creatinine                                          77                  4.2                   37                 0.6 Hyperglycemia                                                 53                  10                    67                 10 Increased amylase                                             37                   8                    43                 4.5 Hypophosphatemia                                              38                  3.7                   27                 4.0 Hyperbilirubinemia (total)                                    15                  0.5                   6                  0.6 Increased lipaseb                                             13                   6                    7                  0.6 Hematology
Anemia                                                        67                  4.2                   84                 11 Neutropenia                                                   27                  2.1                   58                 20 Thrombocytopenia                                            16                  1.0                   38                 4.6 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase.
*
National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).
a
Twelve patients randomized to chemotherapy did not receive study drug.
b
In the ZYKADIA arm, no patients had baseline lipase laboratory assessments, 112 had post-baseline assessments. In the chemotherapy arm, one patient had baseline lipase laboratory assessments but no post-baseline assessment; 49 patients had post-baseline assessments.
Previously Treated ALK-Positive Metastatic NSCLC
The safety of ZYKADIA was evaluated in ASCEND-1, a multicenter, single-arm, open-label clinical study of 255 ALK- positive patients (246 patients with NSCLC and 9 patients with other cancers who received
ZYKADIA at a dose of 750 mg daily under fasted conditions) [see Clinical Studies (14.2)]. The median duration of exposure to ZYKADIA was 6 months.
The study population characteristics were: Median age 53 years, age less than 65 (84%), female (53%), white (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 (89%), brain metastases (49%), and number of prior therapies 2 or more (67%).
Fatal adverse reactions in patients treated with ZYKADIA occurred in 5% of patients, consisting of: Pneumonia (4 patients), respiratory failure, ILD/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis (1 patient each).
Serious adverse reactions reported in 2% or more of patients in ASCEND-1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea.
Dose reductions due to adverse reactions occurred in 59% of patients treated with ZYKADIA. The most frequent adverse reactions, reported in at least 10% of patients, that led to dose reductions or interruptions were: Increased 
ZYK SPI 20FEB22 CL V5                                                                                                  USPI October 2021 ALT (29%), nausea (20%), increased AST (16%), diarrhea (16%), and vomiting (16%). Discontinuation of therapy due to adverse reactions occurred in 10% of patients treated with ZYKADIA . The most frequent adverse reactions that led to discontinuation in 1% or more of patients in ASCEND- 1 were pneumonia, ILD/pneumonitis, and decreased appetite.
Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-1.
Table 5: Adverse Reactions (>10% for All Grades* or ≥ 2% for Grades 3-4) in ALK-Positive Patients Treated With ZYKADIA in ASCEND- 1
ZYKADIA
N=255
All Grades                 Grade 3–4
%                         %
Gastrointestinal **
Diarrhea                                                                     86                        6 Nausea                                                                       80                        4 Vomiting                                                                     60                        4 Abdominal paina                                                              54                        2 Constipation                                                                 29                        0 Esophageal disorderb                                                         16                        1 General
Fatiguec                                                                     52                        5 Metabolism and Nutrition
Decreased appetite                                                           34                        1 Skin
Rashd                                                                       16                        0 Respiratory
Interstitial lung disease/pneumonitis                                       4                         3 Abbreviation: ALK, anaplastic lymphoma kinase.
*National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).
**For frequency of gastrointestinal adverse reactions at the recommended dose of 450 mg with food [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].
a
Abdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, and epigastric discomfort) bEsophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia) c
Fatigue (fatigue and asthenia) d
Rash (rash, maculopapular rash, and acneiform dermatitis)


Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg under fasted conditions included neuropathy (17%; comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy), vision disorder (9%; comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity), prolonged QT interval (4%), and bradycardia (3%). In addition, the adverse reaction of photosensitivity was reported in 1.2% of patients.


ZYK SPI 20FEB22 CL V5                                                                                    USPI October 2021 Table 6: Key Laboratory Abnormalities Occurring in >10% (All Grades*) of ALK-Positive Patients Treated With ZYKADIA in ASCEND- 1
ZYKADIA
N=255
All Grades              Grade 3–4
%                         %
Hematology
Anemia                                                               84                          5 Chemistry
Increased ALT                                                        80                         27 Increased AST                                                        75                         13 Increased creatinine                                                 58                         2 Hyperglycemia                                                        49                         13 Hypophosphatemia                                                     36                         7 Increased lipase                                                     28                         10 Hyperbilirubinemia (total)                                           15                         1 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALK, anaplastic lymphoma kinase.
*National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).

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 (http://sideeffects.health.gov.il).

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