ZYKADIA SIDE EFFECTS
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Gastrointestinal Adverse Reactions
- Hepatotoxicity
- Interstitial Lung Disease/Pneumonitis
- QT Interval Prolongation
- Hyperglycemia
- Bradycardia
- Pancreatitis
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 ASCEND1, 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. 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.
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. 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.
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 1 and 2 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-4.
Table 1: Adverse Reactions (> 10% for All Grades* or ≥ 2% for Grades 3-4) of Patients in ASCEND-4
| ZYKADIA N = 189 |
Chemotherapy N = 175a |
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| 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 |
| 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 |
| Skin | ||||
| Rashe | 21 | 1.1 | 8 | 0.6 |
| Neurologic | ||||
| Headache | 19 | 0.5 | 13 | 1.1 |
| Dizziness | 12 | 1.1 | 10 | 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. aTwelve patients randomized to chemotherapy did not receive study drug. bAbdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, and epigastric discomfort). cEsophageal disorder (dyspepsia, gastroesophageal reflux disease, and dysphagia). dFatigue (fatigue and asthenia). eRash (rash, dermatitis acneiform, rash maculo-papular). fPericarditis (pericardial effusion and pericarditis). |
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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%).
Table 2: Laboratory Abnormalities Occurring in > 10% (All Grades*) of Patients in ASCEND-4
| ZYKADIA N = 189 |
Chemotherapy N = 175a |
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| 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 |
| Hypophosphatemia | 38 | 3.7 | 27 | 4.0 |
| Increased amylase | 37 | 8 | 43 | 4.5 |
| 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). aTwelve patients randomized to chemotherapy did not receive study drug. bIn 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. |
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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). 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 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 3 and 4 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-1.
Table 3: 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 |
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| 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. aAbdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, and epigastric discomfort). bEsophageal disorder (dyspepsia, gastroesophageal reflux disease, and dysphagia). cFatigue (fatigue and asthenia). dRash (rash, maculopapular rash, and acneiform dermatitis). |
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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%).
Table 4: Key Laboratory Abnormalities Occurring in > 10% (All Grades*) of ALK-Positive Patients Treated with ZYKADIA in ASCEND-1
| ZYKADIA N = 255 |
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| 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). |
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SRC: NLM .