The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Severe or Persistent Gastrointestinal Toxicity [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Interstitial Lung Disease/Pneumonitis [see WARNINGS AND PRECAUTIONS]
- QT Interval Prolongation [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]
- Hyperglycemia [see WARNINGS AND PRECAUTIONS]
- Bradycardia [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]
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 safety evaluation of ZYKADIA is based on 255 ALK-positive patients in Study 1 (246 patients with NSCLC and 9 patients with other cancers who received ZYKADIA at a dose of 750 mg daily). 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%), Caucasian (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), ECOG PS 0 or 1 (89%), brain metastasis (49%), and number of prior therapies 2 or more (67%).
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 ALT (29%), nausea (20%), increased AST (16%), diarrhea (16%), and vomiting (16%). Serious adverse drug reactions reported in 2% or more of patients in Study 1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. 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). Discontinuation of therapy due to adverse reactions occurred in 10% of patients treated with ZYKADIA. The most frequent adverse drug reactions that led to discontinuation in 1% or more of patients in Study 1 were pneumonia, ILD/pneumonitis, and decreased appetite.
Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in ZYKADIA-treated patients.
Table 2: Adverse Reactions ( > 10% for All NCI CTCAE* Grades or ≥ 2% for Grades 3-4) in ALK-Positive Patients Treated with ZYKADIA in Study 1
|All Grades %||Grade 3-4 %|
|General disorders and administration site conditions|
|Metabolism and nutrition disorders|
|Skin and subcutaneous tissue disorders|
|Respiratory, thoracic and mediastinal disorders|
|Interstitial lung disease/pneumonitis||4||3|
|*National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03)
aAbdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, epigastric discomfort)
bEsophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia)
cFatigue (fatigue, asthenia)
dRash (rash, maculopapular rash, acneiform dermatitis)
Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 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%).
Table 3: Key Laboratory Abnormalities Occurring in > 10% (All NCI CTCAE Grades) of ALK-Positive Patients Treated with ZYKADIA in Study 1
|All Grades %||Grade 3-4 %|
|Alanine transaminase (ALT) increased||80||27|
|Aspartate transaminase (AST) increased||75||13|
|Bilirubin (total) increased||15||1|