Summary
Commonly reported side effects of crizotinib include: increased serum alanine aminotransferase. Continue reading for a comprehensive list of adverse effects.
Applies to crizotinib: oral capsules.
Side effects include:
ALK-positive metastatic NSCLC (≥25%): Vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated aminotransferase concentrations, fatigue, decreased appetite, upper respiratory infection, dizziness, neuropathy.
ALCL (≥35%): Diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, pruritus.
Grade 3 or 4 laboratory abnormalities (≥15%): Neutropenia, lymphopenia, thrombocytopenia.
For Healthcare Professionals
Applies to crizotinib: oral capsule.
General
The most common adverse reactions in adult patients with non-small cell lung cancer (NSCLC) were vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.
The most common adverse reactions in patients with anaplastic large cell lymphoma (ALCL) were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus. The most common grade 3 to 4 laboratory abnormalities were neutropenia, lymphopenia, and thrombocytopenia.
The most common adverse reactions in adult patients with inflammatory myofibroblastic tumor (IMT) were vision disorders, nausea, and edema. The most common adverse reactions in pediatric patients with IMT were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache.[Ref]
Cardiovascular
Very common (10% or more): Hypertension (up to 31%), hypotension (up to 21%), bradycardia (includes bradycardia, sinus bradycardia, heart rate decreased; up to 26%)
Common (1% to 10%): ECG QT prolonged, QTc prolongation, hypotension, cardiac failure (includes cardiac failure, congestive cardiac failure, ejection fraction decreased, left ventricular failure, pulmonary edema)
Frequency not reported: Septic shock, arrhythmia
Across clinical trials in patients with NSCLC, bradycardia occurred in 13% of 1722 patients treated with this drug; most events were mild in severity. Of 1666 patients with at least 1 postbaseline vital sign assessment, 16% had a pulse rate less than 50 beats per minute.
In 1 study, among 121 patients ages 1 to 21 years treated with this drug, bradycardia was reported in 14% of patients, including grade 3 bradycardia in 0.8% of patients. Of the 26 patients with ALCL, bradycardia (all grade 1) was reported in 19% of patients; of the 14 pediatric patients with IMT, bradycardia was reported in 14% of patients, including grade 3 bradycardia in 7% of patients.
Across clinical trials in patients with NSCLC, 2.1% of 1616 patients had QTcF (corrected QT for heart rate by the Fridericia method) at least 500 ms and 5% of 1582 patients had an increase from baseline QTcF at least 60 ms by automated machine-read evaluation of ECGs.
In 1 study, QTc prolongation was reported in 4.1% of patients, including 8% of patients with ALCL and 7% of pediatric patients with IMT.
Across clinical studies (n=1722), 1.1% of patients treated with this drug had any grade cardiac failure, 0.5% of patients had grade 3 or 4, and 0.2% of patients had fatal outcome.
Dermatologic
Very common (10% or more): Rash (includes maculopapular rash, pustular rash, dermatitis acneiform; up to 57%), pruritus (up to 35%), skin infection (up to 29%)
Uncommon (0.1% to 1%): Photosensitivity
Endocrine
Common (1% to 10%): Decreased blood testosterone (includes hypogonadism, decreased blood testosterone, secondary hypogonadism)
Gastrointestinal
Very common (10% or more): Gastrointestinal toxicity (up to 100%), diarrhea (up to 92%), vomiting (up to 92%), nausea (up to 86%), abdominal pain (includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness; up to 57%), constipation (up to 48%), stomatitis (includes oral pain, oropharyngeal pain, stomatitis; up to 46%), dyspepsia (up to 14%), dysphagia (10%)
Common (1% to 10%): Esophagitis (includes esophagitis, esophageal ulcer)
Uncommon (0.1% to 1%): Gastrointestinal perforation (includes gastrointestinal perforation, intestinal perforation, large intestine perforation)
Nausea (57%), diarrhea (54%), vomiting (51%), and constipation (43%) were the most commonly reported gastrointestinal events in adult patients with either ALK (anaplastic lymphoma kinase)-positive or ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase)-positive NSCLC; most events were mild to moderate in severity. Median times to onset for nausea and vomiting were 3 days, and these events declined in frequency after 3 weeks of therapy; median times to onset for diarrhea and constipation were 13 and 17 days, respectively.
In 26 patients with ALCL, gastrointestinal toxicity occurred in 100% of patients; grade 3 gastrointestinal toxicity occurred in 27% of patients and included diarrhea, nausea, vomiting, and stomatitis. Among 14 pediatric patients with IMT, vomiting, nausea, and diarrhea occurred in 93%, 86%, and 64% of patients, respectively.
Hematologic
Very common (10% or more): Neutropenia (includes neutrophil count decreased, febrile neutropenia, neutropenia; up to 100%), decreased neutrophils (up to 64%), lymphopenia (includes lymphocyte count decreased; up to 58%), anemia (includes anemia, hemoglobin decreased, hypochromic anemia; up to 54%), thrombocytopenia (includes platelet count decreased; up to 38%), leukopenia (includes leukopenia, WBC count decreased; up to 22%)
Common (1% to 10%): Febrile neutropenia
Across studies in patients with either ALK-positive or ROS1-positive advanced NSCLC (N=1722), grade 3 or 4 neutropenia and leukopenia were observed in 12% and 3% of patients treated with this drug, respectively; median time to onset of any grade neutropenia and leukopenia was 89 and 85 days, respectively. In clinical studies with this drug, shifts to grade 3 or 4 decreases in neutrophils and leukocytes were observed in 13% and 4% of patients, respectively. Febrile neutropenia occurred in less than 0.5% of patients.
In clinical studies in 110 pediatric patients with a variety of tumor types, neutropenia and leukopenia were reported in 71% and 63% of patients, respectively; grade 3 or 4 neutropenia and leukopenia were observed in 53% and 16% of patients, respectively. Febrile neutropenia occurred in 3.6% of patients.
Hepatic
Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of the 1722 patients treated with this drug for NSCLC across clinical trials. Concurrent elevations in ALT or AST at least 3 times the upper limit of normal (3 x ULN) and total bilirubin at least 2 x ULN (with normal alkaline phosphatase) occurred in less than 1% of patients treated with this drug. Increased ALT or AST greater than 5 x ULN occurred in 11% and 6% of patients, respectively. Increased transaminases generally occurred within the first 2 months of therapy.
In 1 study, 121 patients ages 1 to 21 years were treated with this drug for relapsed or refractory tumors (including ALCL and IMT); increased ALT and AST were reported in 79% and 71% of patients, respectively, with increased ALT or AST greater than 5 x ULN in 6% of patients each. Of the 26 patients with ALCL treated with this drug, increased ALT and AST were reported in 81% and 65% of patients, respectively, with increases greater than 5 x ULN in 4% each. Of the 14 pediatric patients with IMT treated with this drug, increased AST and ALT were reported in 71% of patients each.
In 1 study, 7 adult patients with IMT were treated with this drug; increased ALT and AST were reported in 43% and 57% of patients, respectively.
Very common (10% or more): Increased ALT (up to 81%), increased AST (up to 66%), elevated transaminases (includes increased ALT, increased AST, increased GGT, increased hepatic enzyme, abnormal hepatic function, abnormal liver function test, increased transaminases; up to 43%)
Common (1% to 10%): Hepatotoxicity, hepatic failure, increased GGT
Metabolic
Very common (10% or more): Hypocalcemia (up to 62%), hypoalbuminemia (up to 54%), hyperglycemia (up to 46%), hypomagnesemia (up to 46%), decreased appetite (up to 42%), hypoglycemia (up to 35%), hypophosphatemia (up to 32%), hypokalemia (up to 31%), hypermagnesemia (up to 27%), hyperkalemia (up to 23%), hypernatremia (up to 19%), hyponatremia (up to 12%), hyperuricemia (up to 12%)
Frequency not reported: Diabetic ketoacidosis
Musculoskeletal
Very common (10% or more): Musculoskeletal pain (includes arthralgia, back pain, myalgia, noncardiac chest pain, pain in extremity; up to 58%), pain in extremity (up to 16%)
Common (1% to 10%): Muscle spasm, muscular weakness
Postmarketing reports: Increased blood creatine phosphokinase
Nervous system
Neuropathy (most commonly sensory in nature) occurred in 25% of 1722 patients; most events (95%) were grade 1 or 2 in severity. Dizziness and dysgeusia were also commonly reported and were primarily grade 1 in severity.
Across clinical trials in patients with NSCLC, grade 3 syncope occurred in 2.4% of patients treated with this drug and in 0.6% of the chemotherapy-treated patients.
Very common (10% or more): Headache (up to 58%), dizziness (includes balance disorder, dizziness, postural dizziness, presyncope; up to 40%), neuropathy (includes dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance, skin burning sensation, burning sensation, formication, hyperesthesia, hypotonia, motor dysfunction, muscle atrophy, neuritis, neurotoxicity, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy; up to 30%), dysgeusia (up to 26%), peripheral neuropathy (up to 12%)
Common (1% to 10%): Syncope
Ocular
Very common (10% or more): Vision disorders (includes diplopia, photophobia, photopsia, reduced visual acuity, blurred vision, vitreous floaters, visual impairment, cyanopsia, heterophoria, visual field defect, halo vision, visual brightness, visual perseveration; up to 92%)
Vision disorders (most commonly visual impairment, photopsia, blurred vision, or vitreous floaters) occurred in 63% of 1722 patients. The majority (95%) of these patients had grade 1 visual adverse reactions; there were 0.8% of patients with grade 3 and 0.2% of patients with grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with this drug in 2 studies reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally occurred within 8 days (range: 1 to 984 days) after the start of therapy. The majority of patients taking this drug in the 2 studies (greater than 50%) reported visual disturbances which occurred at a frequency of 4 to 7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in the VSAQ-ALK questionnaire.
Across all clinical trials in patients with NSCLC, the incidence of grade 4 visual field defect with visual loss was 0.2% of 1722 patients; optic atrophy and optic nerve disorder have been reported as potential causes of visual loss.
In 1 study, visual disorders occurred in 46% of 121 patients, including 65% of 26 patients with ALCL and 50% of 14 patients with IMT; of the 56 patients who experienced visual disorders, 1 pediatric patient with IMT experienced grade 3 myopic optic nerve disorder. The most common visual symptoms were blurred vision and visual impairment.
Other
Very common (10% or more): Edema (includes edema, peripheral edema, face edema, generalized edema, local swelling, localized edema, periorbital edema; up to 55%), pyrexia (up to 50%), fatigue (up to 46%), decreased calcium (up to 36%), pain (includes pain, bone pain, ear pain; up to 29%), chills (up to 23%), increased magnesium (up to 23%), increased alkaline phosphatase (up to 19%), decreased phosphate (up to 15%), decreased weight (10%)
Common (1% to 10%): Increased weight
Frequency not reported: Sepsis
Renal
Very common (10% or more): Increased blood creatinine (includes increased blood creatinine, decreased renal CrCl; up to 100%), decreased estimated glomerular filtration rate (eGFR; up to 76%)
Common (1% to 10%): Renal cyst (includes renal abscess, renal cyst, renal cyst hemorrhage, renal cyst infection), acute renal injury
Uncommon (0.1% to 1%): Renal failure, acute renal failure
The eGFR decreased from a baseline median of 96.42 mL/min/1.73 m2 (n=1681) to a median of 80.23 mL/min/1.73 m2 at 2 weeks (n=1499) in patients with ALK-positive advanced NSCLC who received this drug in clinical trials. No clinically significant changes occurred in median eGFR from 12 to 104 weeks of therapy. Median eGFR slightly increased (83.02 mL/min/1.73 m2) 4 weeks after the last dose of this drug. Overall, decrease in eGFR to less than 90 mL/min/1.73 m2, to less than 60 mL/min/1.73 m2, and to less than 30 mL/min/1.73 m2 occurred in 76%, 38%, and 3.6% of patients, respectively.
Renal cysts occurred in 3% of 1722 patients; the majority of renal cysts were complex in patients treated with this drug. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation; however, across clinical trials, no renal abscesses were confirmed by microbiology tests.
Respiratory
Very common (10% or more): Upper respiratory tract infections (includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, upper respiratory tract infection; up to 64%), cough (includes cough, productive cough; up to 64%), allergic rhinitis (up to 31%)
Common (1% to 10%): Interstitial lung disease (ILD) (includes acute respiratory distress syndrome, ILD, pneumonitis, alveolitis), dyspnea, pulmonary embolism (includes pulmonary artery thrombosis, pulmonary embolism), pneumonia
Frequency not reported: Acute respiratory failure, acute respiratory distress syndrome, respiratory failure
Across clinical trials in patients with NSCLC, 2.9% of patients treated with this drug had ILD of any grade, 1% had grade 3 or 4 ILD, and 0.5% had fatal ILD. ILD generally occurred within 3 months after starting this drug.
In 1 study, among 121 patients ages 1 to 21 years with relapsed or refractory tumors (including ALCL and IMT), ILD occurred in 0.8% of patients.
