XALKORI (crizotinib) Warnings And Precautions

General

ALK or ROS1 Testing

Prior to receiving therapy with XALKORI, patients must be tested and confirmed for either ALK-positive or ROS1-positive locally advanced or metastatic NSCLC using a validated ALK or ROS1 assay, respectively (see CLINICAL TRIALS section). Assessment for ALK-positive or ROS1-positive locally advanced or metastatic NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.

Drug Interactions

Crizotinib is a substrate and inhibitor of CYP3A. The concurrent use of strong CYP3A inhibitors such as ketoconazole may increase crizotinib plasma concentration and should be avoided. The concurrent use of strong CYP3A inducers such as rifampin may decrease crizotinib plasma concentration and should be avoided. The concurrent use of CYP3A substrates with narrow therapeutic indices and associated with life-threatening arrhythmias such as pimozide should be avoided (see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS).

Missed Dose

If a dose of crizotinib is missed, then it should be taken as soon as possible. If it is less than 6 hours until the next dose, then the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.

Effects on Ability to Drive and Use Machinery

Vision disorder, most commonly visual impairment, photopsia, vision blurred, and vitreous floaters, was experienced by 63% of patients in clinical trials of patients with ALK-positive or ROS1-positive NSCLC. Caution should be exercised when driving or operating machinery by patients who experience vision disorders (see DRUG INTERACTIONS).

Carcinogenesis and Mutagenesis

Crizotinib was genotoxic in non-clinical studies (see PART II, TOXICOLOGY; Carcinogenesis, Mutagenesis, Phototoxicity, Reproductive and Developmental Toxicity).

Carcinogenicity studies with crizotinib have not been performed.

Cardiovascular

Bradycardia

Symptomatic bradycardia (e.g. syncope, dizziness, hypotension) can occur in patients receiving XALKORI. In clinical trials of patients with ALK-positive or ROS1-positive NSCLC, bradycardia occurred in 13% of patients treated with XALKORI. A total of 16% of patients with at least 1 postbaseline vital sign assessment had a heart rate less than 50 beats per minute. In Study A8081014, Grade 3 syncope occurred in 0.6% of XALKORI-treated patients and in 1.2% of chemotherapy-treated patients. In Study A8081007, Grade 3 syncope occurred in 3.5% of XALKORI-treated patients and in none of the chemotherapy-treated patients.

The full effect on reduction of heart rate may not develop until several weeks after start of treatment (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; ADVERSE REACTIONS, Electrocardiography and Haemodynamics). Caution should be exercised in patients with a low heart rate at baseline (<60 beats per minute), a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular (AV) block, ischemic heart disease, or congestive heart failure. Avoid using crizotinib in combination with other bradycardic agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia. Monitor heart rate and blood pressure regularly (see Monitoring and Laboratory Tests).

Permanently discontinue for life-threatening symptomatic bradycardia due to XALKORI. If contributing concomitant medication is identified and discontinued, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. Dose modification is not required in cases of asymptomatic bradycardia. For management of patients who develop symptomatic bradycardia, see DOSAGE AND ADMINISTRATION and Monitoring and Laboratory Tests.

QT Interval Prolongation

Prolongation of corrected QT interval without accompanying arrhythmia has been observed (see Electrocardiography and Hemodynamics, ADVERSE REACTIONS).

Pharmacokinetic/pharmacodynamic modeling indicated a concentration-dependent increase in QTcF and decrease in heart rate (HR) (see Electrocardiography and Hemodynamics, ADVERSE REACTIONS). In clinical trials of patients with ALK-positive or ROS1-positive NSCLC, electrocardiogram QT prolonged (all grades) was observed in 3.7% patients. QTcF greater than or equal to 500 msec on at least 2 separate ECGs was observed in 2.1% of patients with at least 1 postbaseline ECG assessment and a maximum increase from baseline QTcF greater than 60msec was observed in 5.0% of patients with a baseline and at least 1 postbaseline ECG assessment. XALKORI should be administered with caution to patients who have a history of, or a predisposition for QTc prolongation, or who are taking medications that are known to prolong the QT interval. When using XALKORI, periodic monitoring of electrocardiogram (ECG) QTc and electrolytes should be considered. In the event of a QTc ≥500 msec (Grade 3), dosing with XALKORI should be withheld until recovery to Grade ≤1 (≤470 msec), then resumed at a reduced dose of 200 mg twice daily. Permanent discontinuation of XALKORI is recommended in the event of a Grade 4 QTc prolongation (≥500 msec [or >60 msec change from baseline] and Torsade de Pointes or polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmias) (see Dose Modification and ADVERSE REACTIONS Sections).

QTc prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of Torsade de Pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de Pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, Torsade de Pointes can progress to ventricular fibrillation and sudden cardiac death. Treatment with XALKORI is not recommended in patients with congenital long QT syndrome, or who are taking medicinal products known to prolong the QT interval (see DRUG INTERACTIONS). Hypokalemia, hypomagnesemia, and hypocalcemia must be corrected prior to XALKORI administration.

Particular care should be exercised when administering XALKORI to patients who are suspected to be at an increased risk of experiencing Torsade de Pointes during treatment with a QTc-prolonging drug.

Risk factors for Torsade de Pointes in the general population include, but are not limited to, the following: female gender; age ≥65 years; baseline prolongation of the QT/QTc interval; presence of genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndromes; family history of sudden cardiac death at <50 years of age; cardiac disease; history of arrhythmias; electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia); bradycardia; acute neurological events (e.g., intracranial or subarachnoid haemorrhage, stroke, intracranial trauma); nutritional deficits; diabetes mellitus; and autonomic neuropathy.

When drugs that prolong the QT/QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.

Crizotinib is a functional antagonist of sodium, potassium, and calcium currents (see DETAILED PHARMACOLOGY; Safety Pharmacology).

Thrombotic Events

Deep vein thrombosis was observed in 4.2% of patients in clinical trials of patients with ALK-positive or ROS1-positive NSCLC. Grade 5 treatment-related adverse events of disseminated intravascular coagulation and deep vein thrombosis in 2 patients (<1%) (1 patient each) (see ADVERSE REACTIONS). XALKORI should be used with caution in patients who are at increased risk of thrombotic events. XALKORI has not been studied in patients who have had myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack within the previous 3 months.

Cardiac Dysfunction

In clinical studies with XALKORI and during post marketing surveillance, severe, life-threatening, or fatal adverse reactions of cardiac failure were reported. Patients, with or without pre-existing cardiac disorders, receiving XALKORI, should be monitored for signs and symptoms of heart failure such as edema, dyspnea, rapid weight gain from fluid retention and chest pain. XALKORI has been associated with edema and dyspnea in clinical trials (see ADVERSE REACTIONS). Dosing interruption, dose reduction, or discontinuation should be considered as appropriate if such symptoms are observed. Consideration should be given to the use of cardiac imaging methodologies to monitor cardiac function during XALKORI treatment.

Gastrointestinal

Nausea (57%), diarrhea (54%), vomiting (51%), and constipation (43%) were the most commonly reported gastrointestinal events in patients in clinical trials of NSCLC (see ADVERSE REACTIONS). Most events were mild to moderate in severity. Median times to onset for nausea and vomiting was 3 days and declined in frequency after 3 weeks of treatment. GI events were manageable through the use of dosing interruption, dose reduction, and/or standard medical therapy. Supportive care may include the use of antiemetic medications. In clinical trials, the most commonly used antiemetic medications were ondansetron and prochlorperazine. Median times to onset for diarrhea and constipation were 13 and 17 days, respectively. Supportive care for diarrhea and constipation may include the use of standard antidiarrheal and laxative medications, respectively.

Hepatic/Biliary/Pancreatic

Drug-induced hepatotoxicity, including hepatic failure, with fatal outcome has occurred in 2 (0.1%) of the 1722 patients treated with XALKORI in clinical trials of patients with ALK-positive or ROS1-positive NSCLC. Concurrent elevations in ALT and/or AST ≥3 x ULN and total bilirubin ≥2 x ULN without significant elevations of alkaline phosphatase (Hy’s Law) have been observed in 8 (<1%) of patients treated with XALKORI in clinical trials. Grade 3 or 4 ALT or AST elevations were observed in 11% and 6% of patients, respectively. Seventeen (1%) patients required permanent discontinuation from treatment associated with elevated transaminases. Transaminase elevations generally occurred within the first 2 months of XALKORI treatment.

Monitor with liver function tests including ALT, AST, and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevation in patients who develop transaminase elevations (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

Neurologic

All-causality neuropathy (motor and sensory, see ADVERSE REACTIONS) was experienced by 25% of patients treated with XALKORI and was mainly Grade 1 or 2 in severity. Median time of onset for neuropathy was 91 days. Neuropathy was effectively managed by dosing interruption with or without dose reduction. Dizziness (25%) and dysgeusia (21%) were also commonly reported in these studies, and were primarily Grade 1 in severity.

Cerebral haemorrhage was reported in 7 (0.4%) of 1722 patients with ALK-positive or ROS1-positive NSCLC. Three cases were fatal. CNS haemorrhage has also been reported in 2 patients treated with crizotinib in a Phase 1/2 trial in pediatric patients, both of whom had previously treated primary intracranial tumors (not an authorized indication), 1 of whom had a fatal outcome.

Neutropenia and leukopenia

In clinical studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC, Grade 3 or 4 neutropenia has been very commonly (12%) reported. Grade 3 or 4 leukopenia has been commonly (3%) reported (see ADVERSE REACTIONS). Less than 0.5% of patients experienced febrile neutropenia in clinical studies with crizotinib. Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs (see DOSAGE AND ADMINISTRATION).

Ophthalmologic

Vision Disorder

Vision disorder, most commonly visual impairment, photopsia, vision blurred, and vitreous floaters, was experienced by 63% of patients treated with XALKORI in clinical trials of patients with either ALK-positive or ROS1-positive advanced NSCLC. Of the 1084 patients who experienced vision disorder, 95% of these patients had Grade 1 visual adverse reactions. There were 5 (0.3%) of patients with a Grade 3 adverse reaction and 1 (0.1%) of patient with a Grade 4 adverse reaction. Seven (0.4%) of patients had a dose interruption and 2 (0.1%) of patients had a dose reduction associated with vision disorder. There were no permanent treatment discontinuations associated with vision disorder for any of the 1722 patients treated with crizotinib.

Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies A8081007 and A8081014 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies A8081007 and A8081014 (>50%) reported visual disturbances which occurred at a frequency of 4-7 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.

Ophthalmological evaluation should be considered if vision disorder persists or worsens in severity. Caution should be exercised when driving or operating machinery by patients who experience vision disorder (see TOXICOLOGY).

Severe Visual Loss

In clinical trials of patients with ALK-positive or ROS1-positive NSCLC, the incidence of Grade 4 vision loss was 0.2% (4/1722). Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss.

Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential benefits to the patient.

Renal

Renal cyst was most commonly complex, and has been reported by 3% of patients treated with XALKORI in clinical trials of patients with ALK-positive or ROS1-positive advanced NSCLC. There were no reports of clinically relevant abnormal urinalyses or renal impairment in these cases, although local invasion beyond the kidney was observed in some patients. The significance is unknown (see ADVERSE REACTIONS). Renal cyst has been associated with permanent discontinuation in 3 (0.2%) patients. Periodic monitoring with imaging and urinalysis should be considered in patients who develop renal cysts.

Respiratory

Interstitial Lung Disease/Pneumonitis

Severe, life-threatening or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. In ALK-positive and ROS1-positive clinical trials, 2.9% of XALKORI-treated patients had any grade ILD/pneumonitis, 1.1% had Grade 3 or 4 ILD/pneumonitis, and 8 patients (0.5%) had fatal cases of ILD/pneumonitis. These cases generally occurred within 3 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Other potential causes of ILD/pneumonitis should be excluded, and XALKORI should be interrupted during these investigations. XALKORI should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis (see DOSAGE AND ADMINISTRATION, Dose Modifications and ADVERSE REACTIONS sections).

Sexual Function/Reproduction

Fertility

Based on reproductive organ findings in toxicology studies, male and female fertility may be impaired by treatment with crizotinib (see PART II, TOXICOLOGY section).

Special Populations

Pregnant Women

There are no adequate and well-controlled studies in pregnant women using XALKORI. XALKORI may cause fetal harm when administered to a pregnant woman. Crizotinib was shown to be fetotoxic but not teratogenic in pregnant rats and rabbits (see PART II, TOXICOLOGY; Carcinogenesis, Mutagenesis, Phototoxicity, Reproductive and Developmental Toxicity).

Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. Adequate contraceptive methods should be used during therapy, and for at least 90 days after completing therapy.

If XALKORI is used during pregnancy, or if the patient or their partner becomes pregnant while receiving XALKORI, then the patient or their partner should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

Nursing Women

There are no adequate and well-controlled studies in nursing women using XALKORI. It is not known whether crizotinib and its metabolites are excreted in human milk. Because many drugs are commonly excreted in human milk, and because of the potential harm to nursing infants due to exposure to crizotinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see PART II, TOXICOLOGY section).

Male Patients

Adequate contraceptive methods should be used by men during therapy, and for at least 90 days after completing therapy. If the patient’s partner becomes pregnant while receiving XALKORI, then the patient and his partner should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

Pediatrics (<18 years of age)

The safety and efficacy of XALKORI in pediatric patients have not been established. In toxicology studies, decreased bone formation in growing long bones was observed in immature rats (see PART II, TOXICOLOGY). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Limited data are available on the use of XALKORI in pediatric patients. XALKORI has been studied in a total of 64 pediatric patients (range: 2.6 – 22 years) with advanced relapsed/refractory solid tumors or ALCL in a phase 1/2 study to explore the pharmacokinetics (PK), pharmacodynamics (PD), safety profile/tolerability and anti-tumor activity. The effectiveness of XALKORI in this pediatric population has not been established. CNS haemorrhage was reported in 2 patients in this trial, both of whom had previously treated primary intracranial tumors (not an authorized indication), 1 of whom had a fatal outcome.

Geriatrics (≥65 years of age)

Of the 171 XALKORI treated ALK-positive NSCLC patients in Study A8081014, 22 (13%) were 65 years or older, and 26 (24%) of the 109 patients who crossed over from chemotherapy to receive XALKORI were 65 years or older. Of the 172 XALKORI-treated ALK-positive NSCLC patients in Study A8081007, 27 (16%) were 65 years or older. Of the 154 patients in Study A8081001, 22 (14%) were 65 years or older. Of the 1063 ALK-positive NSCLC patients in Study A8081005, 173 (16%) were 65 years or older. For ALK-positive NSCLC patients, the frequency of adverse reactions was generally similar for XALKORI-treated patients less than 65 years of age and patients 65 years or older, (though the number of patients in the >65 group was small), with the exception of edema and constipation, which were reported with greater frequency in Study A8081014 among patients 65 years or older. Of the 53 ROS1‑positive NSCLC patients in single arm Study A8081001, 15 (28%) were 65 years of older. The frequency of adverse reactions was generally similar for XALKORI-treated patients less than 65 years of age and patients 65 years or older, with the exception of treatment-related Dysgeusia and Nausea, which were reported with greater frequency in patients 65 years or older. Based on existing data, no overall differences in safety or efficacy was observed between these patients and patients <65 years. No starting dose adjustment is required for patients 65 years or older.

Hepatic Impairment

Treatment with XALKORI should be used with caution in patients with hepatic impairment. Based on a clinical study, no starting dose adjustment of XALKORI is recommended for patients with mild hepatic impairment (either AST > Upper Limit of Normal (ULN) and total bilirubin ≤ULN or any AST and total bilirubin >ULN but ≤1.5×ULN). The starting XALKORI dose for patients with moderate hepatic impairment (any AST and total bilirubin >1.5×ULN and ≤3×ULN) is recommended to be 200 mg twice daily. The starting XALKORI dose for patients with severe hepatic impairment (any AST and total bilirubin >3×ULN) is recommended to be 250 mg once daily. (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Renal Impairment

Based on a PK study, the starting dose of XALKORI should be reduced by 50% (250 mg once daily) in patients with severe renal impairment (CLcr < 30 mL/min) not requiring peritoneal dialysis or hemodialysis. No starting dose adjustment is recommended for patients with mild (CLcr 60-89mL/min) or moderate (CLcr 30-59 mL/min)renal impairment (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY Special Populations and Conditions, Renal Impairment).

No data available for patients with severe renal impairment requiring peritoneal dialysis or hemodialysis (CLcr < 30 mL/min) (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions).

Monitoring and Laboratory Tests

ALK or ROS1 Testing

Prior to receiving therapy with XALKORI, patients must be tested and confirmed for ALK-positive or ROS1-positive locally advanced or metastatic NSCLC using a validated assay (see CLINICAL TRIALS section). Assessment for ALK-positive or ROS1-positive locally advanced NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.

Renal Monitoring

Creatinine levels should be assessed at baseline and monitored periodically during treatment with XALKORI.

Periodic monitoring with imaging and urinalysis should be considered in patients who develop renal cysts.

Liver Function Test Monitoring

Liver function tests including ALT and total bilirubin should be performed before XALKORI administration and monitored every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevation. In patients who develop transaminase elevations, consult Dose Modification section (see DOSAGE AND ADMINISTRATION section).

Cardiac Safety Monitoring

Patients receiving XALKORI should be monitored for heart rate and blood pressure. ECG evaluations should be performed at baseline prior to initiating therapy with XALKORI and should be repeated periodically during treatment with XALKORI, to monitor for decreased heart rate and QTc prolongation (see WARNINGS AND PRECAUTIONS, Cardiovascular; ADVERSE REACTIONS, Electrocardiography and Haemodynamics; DRUG INTERACTIONS). Consultation with a cardiologist should be considered when assessing the QT interval to ensure appropriate treatment decisions.

Electrolyte levels (calcium, potassium, and magnesium) should be assessed at baseline and monitored periodically during treatment with XALKORI, particularly in patients at risk for these electrolyte abnormalities (see WARNINGS AND PRECAUTIONS, Cardiovascular; DRUG INTERACTIONS). Hypocalcemia, hypokalemia, and hypomagnesemia should be corrected prior to XALKORI administration.

Hematologic Monitoring

Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs (see DOSAGE AND ADMINISTRATION).