Xalkori

Crizotinib.

Xalkori also contains the following excipients: Colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate and hard gelatin capsule shells.
The pink opaque capsule shell components contain gelatin, titanium dioxide and red iron oxide.
The white opaque capsule shell components contain gelatin and titanium dioxide.
The printing ink contains shellac, propylene glycol, strong ammonia solution, potassium hydroxide and black iron oxide.

Pharmacology: Pharmacodynamics: Crizotinib is a selective small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) and its oncogenic variants (ie, ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the hepatocyte growth factor receptor (HGFR, c-Met) RTK, ROS1 (c-ros) and recepteur d’Origine nantais (RON) RTKs. Crizotinib demonstrated concentration-dependent inhibition of the kinase activity of ALK, ROS1 and c-Met in biochemical assays and inhibited phosphorylation and modulated kinase-dependent phenotypes in cell-based assays. Crizotinib demonstrated potent and selective growth inhibitory activity and induced apoptosis in tumor cell lines exhibiting ALK fusion events (including EML4-ALK and NPM-ALK), ROS1 fusion events or exhibiting amplification of the ALK or MET gene locus. Crizotinib demonstrated antitumor efficacy, including marked cytoreductive antitumor activity, in mice bearing tumor xenografts that expressed ALK fusion proteins. The antitumor efficacy of crizotinib was dose-dependent and correlated to pharmacodynamic inhibition of phosphorylation of ALK fusion proteins (including EML4-ALK and NPM-ALK) in tumors in vivo.
Pediatric Population: The safety and efficacy of crizotinib in pediatric patients has not been established. Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 7 times human clinical exposure based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.
Clinical Studies: Randomized Phase 3 Study 1007: The use of single-agent crizotinib in the treatment of ALK-positive advanced NSCLC with or without brain metastases was investigated in a multicenter, multinational, randomized, open-label phase 3 study (study 1007). The primary objective of this study was to demonstrate that crizotinib 250 mg orally twice daily was superior to standard-of-care chemotherapy (pemetrexed 500 mg/m² or docetaxel 75 mg/m²) IV every 21 days in prolonging progression-free survival (PFS) in patients with ALK-positive advanced NSCLC who had received 1 prior chemotherapy regimen. Patients were required to have ALK-positive NSCLC as identified by FISH prior to randomization. Patients randomized to chemotherapy could cross over to receive crizotinib in study 1005 upon RECIST-defined disease progression confirmed by independent radiology review (IRR). The primary efficacy endpoint was PFS with disease progression events determined by IRR. Secondary endpoints included objective response rate (ORR) as determined by IRR, duration of response (DR), overall survival (OS) and patient-reported outcomes (PRO).
The full analysis population for study 1007 included 347 patients with ALK-positive advanced NSCLC. One hundred seventy-three (173) patients were randomized to the crizotinib arm (172 patients received crizotinib) and 174 patients were randomized to the chemotherapy arm [99 (58%) patients received pemetrexed and 72 (42%) patients received docetaxel]. Randomization was stratified by ECOG performance status (0-1, 2), brain metastases (present, absent) and prior EGFR tyrosine kinase inhibitor treatment (yes, no). The median duration of study treatment was 31 weeks in the crizotinib arm as compared to 12 weeks in the chemotherapy arm.
Patients could continue treatment as assigned beyond the time of RECIST-defined disease progression, as assessed by IRR, at the discretion of the investigator if the patient was still experiencing clinical benefit. Fifty eight of 84 (69%) crizotinib-treated patients and 17 of 119 (14%) chemotherapy-treated patients continued treatment for at least 3 weeks after objective disease progression.
Key demographic and baseline characteristics for patients in this study were comparable between the crizotinib and chemotherapy arms as shown in Table 1 (see Table 1).

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Crizotinib significantly prolonged PFS compared to chemotherapy as assessed by IRR. The median PFS was 7.7 months for patients randomized to crizotinib and 3 months for patients randomized to chemotherapy. The hazard ratio was 0.487 with a p-value of <0.0001 (1-sided, based on stratified log-rank test). The median PFS for patients treated with crizotinib was 7.7 months and 4.2 months for patients treated with pemetrexed. The hazard ratio was 0.589 with a p-value of 0.0004 (1-sided, based on stratified log-rank test). The median PFS for patients treated with crizotinib was 7.7 months and 2.6 months for patients treated with docetaxel. The hazard ratio was 0.298 with a p-value of <0.0001 (1-sided stratified log-rank test).
Crizotinib also significantly improved IRR-assessed ORR as compared to chemotherapy with a p-value of <0.0001 (2-sided stratified test). The ORR for patients randomized to crizotinib was 65% (95% CI: 58%, 72%) and for patients randomized to chemotherapy was 20% (95% CI: 14%, 26%). The ORR for patients treated with crizotinib was 66% (95% CI: 58%, 73%) and 29% (95% CI: 21%, 39%) for patients treated with pemetrexed, with a p-value of <0.0001 (2-sided stratification test). The ORR for patients treated with crizotinib was 66% (95% CI: 58%, 73%) and 7% (95% CI: 2%, 16%) for patients treated with docetaxel, with a p-value of <0.0001 (2-sided stratified test).
Median DR was 32.1 weeks (95% CI: 26.4 weeks, 42.3 weeks) in the crizotinib arm and 24.4 weeks (95% CI: 15 weeks, 36 weeks) in the chemotherapy arm.
Overall survival data were not mature at the time of analysis.
Efficacy data from randomized phase 3 study 1007 are summarized in Table 2 and the Kaplan-Meier curve for PFS is shown in Figure 1. (See Table 2 and Figure 1.)

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Time to deterioration (TTD) was pre-specified as the first occurrence of a ≥10-point increase in scores from baseline in symptoms of pain (EORTC QLQ-LC13 pain in chest), cough (EORTC QLQ-LC13 cough) or dyspnea (EORTC QLQ-LC13 dyspnea). The median TTD in patient-reported pain in chest, dyspnea or cough as a composite endpoint was 5.6 months (95% CI: 3.4 months, 11 months) in the crizotinib arm compared to 1.4 months (95% CI: 1 month, 1.8 months) in the chemotherapy arm. Treatment with crizotinib was associated with a significantly longer TTD in the symptoms of pain in chest, dyspnea or cough compared to chemotherapy (hazard ratio 0.535; 95% CI: 0.404, 0.709; Hochberg adjusted log-rank p<0.0001).
The change from baseline scores was found to be significantly different between the 2 treatment arms, with a significantly greater improvement observed in global quality of life in the crizotinib arm compared to the chemotherapy arm (overall difference in change from baseline scores 9.84; p<0.0001).

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Single-Arm Studies in ALK-Positive Advanced NSCLC: The use of single-agent crizotinib in the treatment of ALK-positive advanced NSCLC with or without brain metastases was investigated in 2 multicenter, multinational, single-arm studies (studies 1001 and 1005). Patients enrolled into these studies had received prior systemic therapy, with the exception of 16 patients in study 1001 and 3 patients in study 1005 who had no prior systemic treatment for locally advanced or metastatic disease. The primary efficacy endpoint in both studies was ORR according to RECIST. Secondary endpoints included time to tumor response (TTR), DR, PFS and OS. Patients received crizotinib 250 mg orally twice daily. Demographic and disease characteristics for studies 1001 and 1005 are provided in Table 3 (see Table 3).

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In study 1001, patients with advanced NSCLC were required to have ALK-positive tumors prior to entering the clinical trial. ALK-positive NSCLC was identified using a number of local clinical trial assays.
One hundred nineteen (119) patients with ALK-positive advanced NSCLC were enrolled into study 1001 at the time of data cutoff. The median duration of treatment was 32 weeks. There were 2 complete responses and 69 partial responses for an ORR of 61%. The median DR was 48.1 weeks. Fifty-five percent (55%) of objective tumor responses were achieved during the first 8 weeks of treatment.
In study 1005, patients with advanced NSCLC were required to have ALK-positive tumors prior to entering the clinical trial. For most patients, ALK-positive NSCLC was identified by FISH.
Nine hundred thirty-four (934) patients with ALK-positive advanced NSCLC were treated with crizotinib in study 1005 at the time of data cutoff. The median duration of treatment for these patients was 23 weeks. Patients could continue treatment as assigned beyond the time of RECIST-defined disease progression at the discretion of the investigator if the benefit/risk assessment justified continuation of treatment. Seventy-seven of 106 patients (73%) continued crizotinib treatment for at least 3 weeks after objective disease progression.
Seven hundred sixty-five (765) patients with ALK-positive advanced NSCLC from study 1005 were both evaluable for response and identified by the same FISH assay used in randomized phase 3 study 1007. There were 8 complete responses and 357 partial responses for an ORR of 48%. The median DR was 47.3 weeks. Eighty-three percent (83%) of objective tumor responses were achieved within the first 12 weeks of treatment.
Efficacy data from studies 1001 and 1005 are provided in Table 4. (See Table 4.)

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Pharmacokinetics: Absorption: Following oral single dose administration in the fasted state, crizotinib is absorbed with median time to achieve peak concentrations of 4-6 hrs. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable with a median accumulation ratio of 4.8. The absolute bioavailability of crizotinib was determined to be 43% (range: 32-66%) following the administration of a single 250-mg oral dose.
A high-fat meal reduced crizotinib AUC_inf and C_max by approximately 14% when a 250-mg single dose was given to healthy volunteers. Crizotinib can be administered with or without food (see Dosage & Administration).
Distribution: The geometric mean volume of distribution (V_ss) of crizotinib was 1772 L following IV administration of a 50-mg dose, indicating extensive distribution into tissues from the plasma. Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood to-plasma concentration ratio is approximately 1.
Metabolism: In vitro studies demonstrated that CYP3A4/5 were the major enzymes involved in the metabolic clearance of crizotinib. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent phase 2 conjugation of O-dealkylated metabolites.
In vitro studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP2B6 and CYP3A.
Elimination: Following single doses of crizotinib, the apparent plasma terminal half-life (t_½) of crizotinib was 42 hrs in patients. Following the administration of a single 250-mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.
The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/hr) after 250 mg twice daily than that after a single 250-mg oral dose (100 L/hr), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.
Drug Interactions: Co-administration of Crizotinib and CYP3A Substrates: Crizotinib has been identified as an inhibitor of CYP3A both in vitro and in vivo. Following 28 days of crizotinib dosing at 250 mg taken twice daily in cancer patients, the oral midazolam AUC was 3.7-fold (90% CI: 2.63-5.07) those seen when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A (see Interactions).
Co-administration of Crizotinib and CYP3A Inhibitors: Co-administration of a single 150-mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib AUC_inf and C_max values that were approximately 3.2- and 1.4-fold, respectively, those seen when crizotinib was administered alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been established (see Interactions).
Co-administration of Crizotinib and CYP3A Inducers: Co-administration of a single 250-mg crizotinib dose with rifampin (600 mg once daily), a strong CYP3A inducer, resulted in 82% and 69% decreases in crizotinib AUC_inf and C_max, respectively, compared to when crizotinib was given alone. However, the effect of CYP3A inducers on steady-state crizotinib exposure has not been established (see Interactions).
Co-administration of Crizotinib with Agents that Increase Gastric pH: The aqueous solubility of crizotinib is pH dependent, with low (acidic) pH resulting in higher solubility. Administration of a single 250-mg crizotinib dose following treatment with esomeprazole 40 mg once daily for 5 days resulted in an approximately 10% decrease in crizotinib total exposure (AUC_inf) and no change in peak exposure (C_max); the extent of the change in total exposure was not clinically meaningful. Therefore, starting dose adjustment is not required when crizotinib is co-administered with agents that increase gastric pH (eg, proton-pump inhibitors, H₂-blockers or antacids).
Co-administration with Other CYP Substrates: In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6.
Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are predominantly metabolized by CYP2B6. In vitro studies in human hepatocytes indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated induction of the metabolism of drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A.
Co-administration with UGT Substrates: In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7.
Co-administration with Drugs that are Substrates of Transporters: Crizotinib is an inhibitor of P-gp in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are substrates of P-gp.
Crizotinib is an inhibitor of OCT1 and OCT2 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are substrates of OCT1 or OCT2.
In vitro, crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3, or the renal uptake transport proteins OAT1 or OAT3 at clinically relevant concentrations. Therefore, clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the hepatic or renal uptake of drugs that are substrates for these transporters.
Effect on Other Transport Proteins: In vitro, crizotinib is not an inhibitor of BSEP at clinically relevant concentrations.
Pharmacokinetics in Special Patient Groups: Hepatic Insufficiency: As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, crizotinib has not been studied in patients with hepatic impairment. Clinical studies that were conducted excluded patients with ALT or AST >2.5 x ULN or, if due to underlying malignancy, >5 x ULN or with total bilirubin >1.5 x ULN (see Table 6 and Dosage & Administration). The population pharmacokinetic analysis using the data from these studies indicated that baseline total bilirubin or AST levels did not have a clinically meaningful effect on the pharmacokinetics of crizotinib.
Renal Insufficiency: Patients with mild (60≤ CrCl <90 mL/min) and moderate (30≤ CrCl <60 mL/min) renal impairment were enrolled in single-arm studies 1001 and 1005. The effect of renal function as measured by baseline CrCl on observed crizotinib steady state trough concentrations (C_trough, _ss) was evaluated. In study 1001, the adjusted geometric mean of plasma C_trough, _ss in mild (N=35) and moderate (N=8) renal impairment patients were 5.1% and 11% higher, respectively, than those in patients with normal renal function. In study 1005, the adjusted geometric mean C_trough, _ss of crizotinib in mild (N=191) and moderate (N=65) renal impairment groups were 9.1% and 15% higher, respectively, than those in patients with normal renal function. In addition, the population pharmacokinetic analysis from studies 1001, 1005 and 1007 indicated CrCl did not have a clinically meaningful effect on the pharmacokinetics of crizotinib. Due to the small size of the increases in crizotinib exposure (5-15%), no starting dose adjustment is recommended for patients with mild or moderate renal impairment. After a single 250-mg dose in subjects with severe renal impairment (CrCl <30 mL/min) not requiring peritoneal dialysis or hemodialysis, crizotinib AUC and C_max increased by 79% and 34%, respectively, compared to those with normal renal function. An adjustment of the dose of crizotinib is recommended when administering crizotinib to patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis (see Dosage & Administration and Precautions).
Age: Based on the population pharmacokinetic analysis from studies 1001, 1005 and 1007, age has no effect on crizotinib pharmacokinetics.
Body Weight and Gender: Based on the population pharmacokinetic analysis from studies 1001, 1005 and 1007, there was no clinically meaningful effect of body weight or gender on crizotinib pharmacokinetics.
Ethnicity: Based on the population pharmacokinetic analysis from studies 1001, 1005 and 1007, the predicted steady-state AUC (95% CI) was 23-37% higher in Asian patients (n=523) than in non-Asian patients (n=691).
Cardiac Electrophysiology: The QT interval prolongation potential of crizotinib was assessed in all patients who received crizotinib 250 mg twice daily. Serial ECGs in triplicate were collected following a single dose and at steady state to evaluate the effect of crizotinib on QT intervals. Sixteen of 1167 patients (1.4%) were found to have QTcF (corrected QT by the Fridericia method) ≥500 msec, and 51 of 1136 patients (4.4%) had an increase from baseline QTcF ≥60 msec by automated machine-read evaluation of ECG. A central tendency analysis of the QTcF data demonstrated that the highest upper bound of the 2-sided 90% CI for QTcF was <15 msec at the protocol pre-specified time points. A pharmacokinetic/pharmacodynamic analysis suggested a relationship between crizotinib plasma concentration and QTc.
Toxicology: Preclinical Safety Data: Genotoxicity: Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. Crizotinib was aneugenic in an in vitro micronucleus assay in Chinese hamster ovary cells and in an in vitro human lymphocyte chromosome aberration assay. Small increases of structural chromosomal aberrations at cytotoxic concentrations were seen in human lymphocytes. In the rat bone marrow in vivo, increases in micronuclei were only seen at doses significantly exceeding the expected human exposure. Increases in micronuclei were observed in rats at 250 mg/kg/day (approximately 7 times the AUC at the recommended human dose).
Carcinogenicity: Carcinogenicity studies with crizotinib have not been performed.
Fertility: No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given ≥50 mg/kg/day for 28 days (approximately 2-fold human clinical exposure based on AUC). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day for 3 days.

Treatment of advanced non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by FISH assay.

ALK Testing: Detection of ALK-positive NSCLC is necessary for selection of patients for treatment with crizotinib because these are the only patients for whom benefit has been shown.
Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.
Recommended Dosing: The recommended dose schedule of crizotinib is 250 mg taken orally twice daily continuously. Continue treatment as long as the patient is deriving clinical benefit from therapy. Crizotinib may be taken with or without food (see Pharmacology: Pharmacokinetics under Actions). If a dose of crizotinib is missed, then it should be taken as soon as the patient remembers unless it is <6 hrs until the next dose, in which case 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.
Dose Modification: Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then the dose of crizotinib should be reduced to 200 mg taken orally twice daily, and if further dose reduction is necessary, modified to 250 mg taken orally once daily. Dose reduction guidelines for hematologic and non-hematologic toxicities are provided in Tables 5 and 6. (See Tables 5 and 6.)

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Hepatic Impairment: As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, crizotinib has not been studied in patients with hepatic impairment. Clinical studies that were conducted excluded patients with AST or ALT >2.5 x ULN, or if due to underlying malignancy, >5 x ULN or with total bilirubin >1.5 x ULN. Treatment with crizotinib should be used with caution in patients with hepatic impairment (see Table 6 and Adverse Reactions).
Renal Impairment: No starting dose adjustment is needed for patients with mild (60≤ CrCl <90 mL/min) or moderate renal impairment (30≤ CrCl <60 mL/min), since the population pharmacokinetic analysis indicated no clinically meaningful changes in steady-state crizotinib exposure in these patients. Crizotinib plasma concentrations may be increased in patients with severe renal impairment (CrCl <30 mL/min). The crizotinib dose should be adjusted to 250 mg taken orally once daily in patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis. The dose may be increased to 200 mg twice daily based on individual safety and tolerability after at least 4 weeks of treatment (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Children: The safety and efficacy of crizotinib in pediatric patients have not been established.
Elderly: Of the 172 crizotinib-treated patients in randomized phase 3 study 1007, 27 (16%) were ≥65 years. Of the 119 patients in study 1001, 16 (13%) were ≥65 years. Of the 934 patients in study 1005, 152 (16%) were ≥65 years. No overall differences in safety or efficacy were observed in comparison with younger patients.
Administration: Xalkori may be taken with or without food. Swallow capsules whole.

Treatment of overdose with crizotinib should consist of general supportive measures. There is no antidote for crizotinib.

Hypersensitivity to crizotinib or to any of the excipients of Xalkori.

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. These cases have occurred during crizotinib treatment in <1% of patients in clinical trials. Concurrent elevations in ALT >3 x ULN and total bilirubin >2 x ULN without elevated alkaline phosphatase have been observed in <1% patients in clinical trials. Increases to grade 3 or 4 ALT elevation were observed in 17% of patients in randomized phase 3 study 1007, 4% of patients in study 1001 and 8% of patients in study 1005. Grade 3 and 4 elevations were generally asymptomatic and reversible upon dosing interruption. Patients usually resumed treatment at a lower dose without recurrence; however, 2 patients from randomized phase 3 study 1007 (1%), 1 patient from study 1001 (<1%), and 6 patients from study 1005 (<1%) required permanent discontinuation from treatment. Transaminase elevations generally occurred within the first 2 months of treatment. Liver function tests including ALT and total bilirubin should be monitored once a month and as clinically indicated, with more frequent repeat testing for grades 2, 3 or 4 elevation. For patients who develop transaminase elevations, see Dosage & Administration.
Interstitial Lung Disease (Pneumonitis): Crizotinib has been associated with severe, life-threatening or fatal interstitial lung disease (ILD)/pneumonitis in clinical trials with a frequency of 17 in 1225 (1.4%) patients across randomized phase 3 study 1007, study 1001 and study 1005. These cases generally occurred within 2 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. Crizotinib should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis (see Dosage & Administration).
QT Interval Prolongation: Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. Crizotinib should be administered with caution to patients who have a history of or predisposition for QTc prolongation, or who are taking medications that are known to prolong the QT interval. When using crizotinib in these patients, periodic monitoring with electrocardiograms and electrolytes should be considered. For patients who develop QTc prolongation, see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration.
Bradycardia: Bradycardia has been reported in clinical studies, and it was usually asymptomatic. The full effect of crizotinib on pulse rate may not develop until several weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic agents (eg, β-blockers, non-dihydropyridine calcium channel blockers eg, verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia (syncope, dizziness, hypotension). Monthly monitoring of pulse rate and blood pressure is recommended. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia, crizotinib should be held and the use of concomitant medications should be re-evaluated. For management of patients who develop symptomatic bradycardia, see Dosage & Administration and Adverse Reactions.
Renal Impairment: If patients have severe renal impairment not requiring peritoneal dialysis or hemodialysis, the dose of crizotinib should be adjusted (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
ALK Testing: Detection of ALK-positive NSCLC using a FISH assay, indicated for this use is necessary for selection of patients for treatment with Xalkori.
Effects on the Ability to Drive or Operate Machinery: No studies on the effect of crizotinib on the ability to drive and use machines have been performed. However, caution should be exercised when driving or operating machinery by patients who experience vision disorder, dizziness or fatigue while taking crizotinib (see Adverse Reactions).
Use in Pregnancy & Lactation: Fertility: Based on non-clinical safety findings, male and female fertility may be compromised by treatment with crizotinib (see Toxicology: Preclinical Safety Data under Actions).
Crizotinib may cause fetal harm when administered to a pregnant woman. Crizotinib was not shown to be teratogenic in pregnant rats or rabbits. Reduced fetal body weights were considered adverse effects in the rat and rabbit at 200 and 60 mg/kg/day, respectively (approximately 2-fold human clinical exposure based on AUC).
There are no adequate and well-controlled studies in pregnant women using crizotinib. Women of childbearing potential should be advised to avoid becoming pregnant while receiving crizotinib. Women of childbearing potential who are receiving Xalkori, or partners of women of childbearing potential receiving it, should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy.
Female patients taking crizotinib during pregnancy or who become pregnant while taking crizotinib should be apprised of the potential hazard to a fetus. Male patients taking crizotinib should also be apprised of the potential hazard to a fetus if their partner is or should become pregnant.
It is not known whether crizotinib and its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from 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.

Use in Pregnancy & Lactation: Fertility: Based on non-clinical safety findings, male and female fertility may be compromised by treatment with crizotinib (see Toxicology: Preclinical Safety Data under Actions).
Crizotinib may cause fetal harm when administered to a pregnant woman. Crizotinib was not shown to be teratogenic in pregnant rats or rabbits. Reduced fetal body weights were considered adverse effects in the rat and rabbit at 200 and 60 mg/kg/day, respectively (approximately 2-fold human clinical exposure based on AUC).
There are no adequate and well-controlled studies in pregnant women using crizotinib. Women of childbearing potential should be advised to avoid becoming pregnant while receiving crizotinib. Women of childbearing potential who are receiving Xalkori, or partners of women of childbearing potential receiving it, should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy.
Female patients taking crizotinib during pregnancy or who become pregnant while taking crizotinib should be apprised of the potential hazard to a fetus. Male patients taking crizotinib should also be apprised of the potential hazard to a fetus if their partner is or should become pregnant.
It is not known whether crizotinib and its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from 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.

Summary of Safety Profile: The data described as follows reflect exposure to crizotinib in 172 patients with ALK-positive advanced NSCLC who participated in randomized phase 3 study 1007 and in 1053 patients with ALK-positive advanced NSCLC who participated in 2 single-arm clinical trials (studies 1001 and 1005). These patients received a starting oral dose of 250 mg twice daily continuously. In study 1007, the median duration of study treatment was 31 weeks for patients on crizotinib. In study 1001, the median duration of treatment was 32 weeks. In study 1005, the median duration of treatment was 23 weeks.
Clinical Trials Experience: The most serious adverse reactions in patients with ALK-positive advanced NSCLC are hepatotoxicity, ILD/pneumonitis and QT interval prolongation (see Precautions). The most common adverse reactions (≥25%) in patients with ALK-positive NSCLC are vision disorder, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases and fatigue.
The adverse drug reactions listed as follows are presented by system organ class and frequency categories, defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100) or rare (≥1/10,000 to <1/1000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and Lymphatic System Disorders: Very Common: Neutropenia (febrile neutropenia, decreased neutrophil count) (15%). Common: Leukopenia (6%).
Metabolism and Nutrition Disorders: Very Common: Decreased appetite (25%).
Nervous System Disorders: Very Common: Neuropathy (burning sensation, dysaesthesia, formication, gait disturbance, hyperaesthesia, hypoaesthesia, hypotonia, motor dysfunction, muscle atrophy, muscular weakness, neuralgia, neuritis, peripheral neuropathy, neurotoxicity, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, peroneal nerve palsy, polyneuropathy, sensory disturbance, burning skin sensation) (19%), dizziness (balance disorder, postural dizziness, presyncope) (20%), dysgeusia (19%).
Eye Disorders: Very Common: Vision disorder (diplopia, halo vision, photophobia, photopsia, blurred vision, reduced visual acuity, visual brightness, visual field defect, visual impairment, vitreous floaters) (56%).
Cardiac Disorders: Common: Prolonged QT electrocardiogram (3%), bradycardia (decreased heart rate, sinus bradycardia) (6%).
Respiratory, Thoracic and Mediastinal Disorders: Common: Interstitial lung disease (acute respiratory distress syndrome, pneumonitis) (3%).
Gastrointestinal Disorders: Very Common: Vomiting (46%), nausea (51%), diarrhea (48%), constipation (39%). Common: Dyspepsia (7%).
Hepatobiliary Disorders: Very Common: Elevated transaminases (increased alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, hepatic enzyme and transaminases, abnormal hepatic function and liver function test) (25%). Common: Increased blood alkaline phosphatase (6%). Uncommon: Hepatic failure (<1%).
Skin and Subcutaneous Tissue Disorders: Very common: Rash (10%).
Renal and Urinary Disorders: Common: Renal cyst (renal abscess, cyst) (2%).
General Disorders and Administration Site Conditions: Very Common: Fatigue (26%), edema (face and generalised edema, local swelling, localised edema, peripheral and periorbital edema) (38%).
Dosing interruptions and reductions due to investigator-assessed treatment-related adverse events occurred in 54 (31%) and 26 (15%) crizotinib-treated patients in randomized phase 3 study 1007, respectively. Investigator-assessed treatment-related adverse events resulting in permanent discontinuation occurred in 11 (6%) patients on crizotinib.
Dosing interruptions and reductions due to investigator-assessed treatment-related adverse events occurred in 14 (12%) patients and 6 (5%) patients in study 1001, respectively. Investigator assessed treatment-related adverse events resulting in permanent discontinuation occurred in 3 (3%) patients in study 1001.
Dosing interruptions and reductions due to investigator-assessed treatment-related adverse events occurred in 212 (23%) patients and 116 (12%) patients in study 1005, respectively. Investigator assessed treatment-related adverse events resulting in permanent discontinuation occurred in 45 (5%) patients in study 1005.
Description of Selected Adverse Reactions: Visual Effects: Treatment-emergent all-causality vision disorder, most commonly visual impairment, photopsia, blurred vision and vitreous floaters, was experienced by 103 (60%) patients in randomized phase 3 study 1007 and 75 (63%) and 513 (55%) patients in studies 1001 and 1005, respectively. Investigator-assessed treatment-related vision disorder was reported for 101 (59%) patients in randomized phase 3 study 1007, and 74 (62%) and 496 (53%) patients in studies 1001, and 1005, respectively. Greater than 96% of these patients had events that were mild in severity with median times to onset of 5, 13 and 7 days in studies 1007, 1001 and 1005, respectively. Ophthalmological evaluation should be considered if vision disorder persists or worsens in severity.
Four (4) patients had temporary treatment discontinuation and 1 patient had dose reduction for vision disorder, all from study 1005. Permanent discontinuation from crizotinib treatment due to vision disorder was not required for any patients in studies 1007, 1001 and 1005.
Gastrointestinal Effects: Nausea, diarrhea, vomiting and constipation were the most commonly reported gastrointestinal events. Median times to onset for nausea and vomiting was 2-3 days. Most events were mild to moderate in severity and declined in frequency after 3-4 weeks of treatment. Supportive care should include the use of antiemetic medications. In clinical trials, the most commonly used antiemetic medications were ondansetron and prochlorperazine. Diarrhea and constipation were primarily mild to moderate in severity. Supportive care for diarrhea and constipation should include the use of standard antidiarrheal and laxative medications, respectively.
Nervous System Effects: Treatment-emergent all-causality neuropathy as previously mentioned was experienced by 33 (19%) patients in randomized phase 3 study 1007 and 24 (20%) and 178 (19%) patients in studies 1001 and 1005, respectively. Investigator-assessed treatment-related neuropathy was experienced by 14 (8%) of patients in randomized phase 3 study 1007 and 13 (11%) and 95 (10%) patients in studies 1001 and 1005, respectively, and was primarily grade 1 in severity. Dizziness and dysgeusia were also very commonly reported in these studies and were primarily grade 1 in severity.
Bradycardia: Treatment-emergent all-causality bradycardia was experienced by 8 (5%) patients in randomized phase 3 study 1007 and 8 (7%) and 57 (6%) patients in studies 1001 and 1005, respectively. Investigator-assessed treatment-related bradycardia was experienced by 7 (4%) patients in randomized phase 3 study 1007 and 6 (5%) and 49 (5%) patients in studies 1001 and 1005, respectively. The majority of these cases were grade 1 or 2 in severity. In studies 1007, 1001 and 1005, 19 of 170 (11%) patients, 16 of 114 (14%) patients and 90 of 890 (10%) patients had a pulse rate <50 bpm. The use of concomitant medications associated with bradycardia should be carefully evaluated. Patients who develop symptomatic bradycardia should be managed as recommended in Dosage & Administration and Precautions (see Dosage & Administration and Precautions).
Renal Cyst: Treatment-emergent all-causality complex renal cysts were experienced by 7 (4%) patients in randomized phase 3 study 1007 and 0 and 12 (1%) patients in studies 1001 and 1005, respectively. Investigator-assessed treatment-related complex renal cysts were reported in 7 (4%) patients in randomized phase 3 study 1007 and 11 (1%) patients in study 1005. There were no reports of clinically relevant abnormal urinalyses or renal impairment in these cases, although local cystic invasion beyond the kidney was observed in some patients. Periodic monitoring with imaging and urinalysis should be considered in patients who develop renal cysts.
Laboratory Abnormalities/Testing Hematologic Laboratory Abnormalities: In randomized phase 3 study 1007, shifts to grade 3 or 4 decreases in leukocytes and neutrophils were observed at frequencies of 5% and 13%, respectively. In study 1001, shifts to grade 3 or 4 decreases in leukocytes and neutrophils were each observed in patients at frequencies of <4%. In study 1005, shifts to grade 3 or 4 decreases in leukocytes and neutrophils were observed in patients at frequencies of <3% and 8%, respectively. 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. In patients who develop hematologic laboratory abnormalities, see Dosage & Administration.
Hepatic Laboratory Abnormalities: In randomized phase 3 study 1007, increases to grade 3 or 4 ALT, AST and alkaline phosphatase were observed in patients at frequencies of 17%, 9% and 2%, respectively. In study 1001, increases to grade 3 or 4 ALT, AST and alkaline phosphatase were observed in patients at frequencies of 5%, 3% and 0%, respectively. In study 1005, increases to grade 3 or 4 ALT, AST and alkaline phosphatase were observed in patients at frequencies of 8%, 4% and 2%, respectively. Patients should be monitored for hepatotoxicity and managed as recommended in Precautions (see Precautions).

Crizotinib is a substrate of CYP3A4/5 and also a moderate inhibitor of CYP3A. In vitro studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP3A.
Agents that May Increase Crizotinib Plasma Concentrations: Co-administration of crizotinib with strong CYP3A inhibitors may increase crizotinib plasma concentrations. The concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin and voriconazole, should be avoided (see Dosage & Administration). Grapefruit or grapefruit juice may also increase plasma concentrations of crizotinib and should be avoided.
Agents that May Decrease Crizotinib Plasma Concentrations: Co-administration of crizotinib with strong CYP3A inducers may decrease crizotinib plasma concentrations. The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin and St. John’s wort, should be avoided (see Dosage & Administration).
Agents whose Plasma Concentrations May be Altered by Crizotinib: Crizotinib has been identified as an inhibitor of CYP3A both in vitro and in vivo. Caution should be exercised in administering crizotinib in combination with drugs that are predominantly metabolized by CYP3A, particularly those, CYP3A substrates that have narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, fentanyl, quinidine, sirolimus and tacrolimus.
Co-administration of crizotinib should be avoided with CYP3A substrates that have narrow therapeutic indices and are associated with life-threatening arrhythmias, including but not limited to dihydroergotamine, ergotamine, astemizole, cisapride, terfenadine and pimozide.

Store at controlled room temperature 15-30ºC.

Targeted Cancer Therapy

L01ED01 - crizotinib ; Belongs to the class of anaplastic lymphoma kinase (ALK) inhibitors. Used in the treatment of cancer.

S

Cap 200 mg (hard gelatin, size 1, white opaque/pink opaque containing a white to pale yellow powder, printed with "CRZ 200" on the body and "Pfizer" on the cap in black ink) x 10's. 250 mg (hard gelatin, size 0, pink opaque/pink opaque containing a white to pale yellow powder, printed with "CRZ 250" on the body and "Pfizer" on the cap in black ink) x 10's.