Xalkori
(crizotinib)Dosage & Administration
Xalkori Prescribing Information
ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer
XALKORI is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test [see Dosage and Administration (2.1)].
Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma
XALKORI is indicated for the treatment of pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive.
Limitations of Use: The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.
Unresectable, Recurrent, or Refractory ALK-Positive Inflammatory Myofibroblastic Tumor
XALKORI is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.
Patient Selection
Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS1 positivity in tumor specimens [see Clinical Studies (14.1, 14.2, 14.3)].
Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at http://www.fda.gov/companiondiagnostics.
Recommended Testing During Treatment with XALKORI
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- Monitor liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (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 increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases [see Warnings and Precautions (5.1)].
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- Monitor complete blood counts including differential weekly for the first month of therapy and then at least monthly, with more frequent monitoring if Grade 3 or 4 abnormalities, fever, or infection occur [see Adverse Reactions (6.1)].
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- For pediatric and young adult patients with ALCL or pediatric patients with IMT, obtain baseline and follow-up ophthalmologic examinations including retinal examination within 1 month of starting XALKORI and every 3 months thereafter [see Warnings and Precautions (5.5)].
Recommended Dosage
The recommended dosage of XALKORI is provided in Table 1.
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Indication | Recommended Dosage of XALKORI |
ALK- or ROS1-Positive Metastatic NSCLC | Adults: |
Relapsed or Refractory, Systemic ALK-Positive ALCL | Pediatric Patients and Young Adults: |
Unresectable, Recurrent, or Refractory ALK-Positive IMT | Adults: |
Pediatric Patients: | |
Recommended Dosage for Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC
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- The recommended dosage for adult patients with ALK- or ROS1-positive metastatic NSCLC is XALKORI capsules 250 mg orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs.
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- For adults who cannot swallow capsules, the recommended dosage of XALKORI pellets is 250 mg (2 x 50 mg + 1 x 150 mg) orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs.
Recommended Dosage for Pediatric and Young Adult Patients with ALK-Positive ALCL
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- The recommended dosage for pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic ALK-positive ALCL is based on body surface area (BSA) and is provided in Table 2.
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- Administer XALKORI capsules or pellets orally, twice daily, with or without food until disease progression or unacceptable toxicity occurs.
Table 2 provides the dosage based on body surface area (BSA) for XALKORI capsules or pellets.
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Body Surface Area (BSA) | Recommended XALKORI Dosage to Achieve 280 mg/m2 Twice Daily | Dose Strength Combinations of XALKORI Pellets to Administer * | Dose Strength Combinations of XALKORI Capsules to Administer |
0.38 to 0.46 m2 | 120 mg twice daily | 1 x 20 mg + 2 x 50 mg | --- |
0.47 to 0.51 m2 | 140 mg twice daily | 2 x 20 mg + 2 x 50 mg | --- |
0.52 to 0.61 m2 | 150 mg twice daily | 1 x 150 mg | --- |
0.62 to 0.80 m2 | 200 mg twice daily | 1 x 50 mg + 1 x 150 mg | --- |
0.81 to 0.97 m2 | 250 mg twice daily | 2 x 50 mg + 1 x 150 mg | --- |
0.98 to 1.16 m2 | 300 mg twice daily | 2 x 150 mg | --- |
1.17 to 1.33 m2 | 350 mg twice daily | 1 x 50 mg + 2 x 150 mg | --- |
1.34 to 1.51 m2 | 400 mg twice daily | 2 x 50 mg + 2 x 150 mg | 2 x 200 mg |
1.52 to 1.69 m2 | 450 mg twice daily | 3 x 150 mg | 1 x 200 mg + 1 x 250 mg |
1.7 m2 or greater | 500 mg twice daily | 1 x 50 mg + 3 x 150 mg | 2 x 250 mg |
Recommended Dosage for Pediatric and Adult Patients with ALK-Positive IMT
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- The recommended dosage for adult patients with unresectable, recurrent, or refractory ALK-positive IMT is provided in Table 1.
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- The recommended dosage for pediatric patients 1 year of age and older with unresectable, recurrent, or refractory ALK-positive IMT is based on BSA and is provided in Table 3.
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- Administer XALKORI capsules or pellets orally twice daily, with or without food, until disease progression or unacceptable toxicity occurs.
Table 3 provides the dosage based on BSA for XALKORI capsules or pellets.
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Body Surface Area (BSA) | Recommended XALKORI Dosage to Achieve 280 mg/m2 Twice Daily | Dose Strength Combinations of XALKORI Pellets to Administer * | Dose Strength Combinations of XALKORI Capsules to Administer |
0.38 to 0.46 m2 | 120 mg twice daily | 1 x 20 mg + 2 x 50 mg | --- |
0.47 to 0.51 m2 | 140 mg twice daily | 2 x 20 mg + 2 x 50 mg | --- |
0.52 to 0.61 m2 | 150 mg twice daily | 1 x 150 mg | --- |
0.62 to 0.80 m2 | 200 mg twice daily | 1 x 50 mg + 1 x 150 mg | --- |
0.81 to 0.97 m2 | 250 mg twice daily | 2 x 50 mg + 1 x 150 mg | --- |
0.98 to 1.16 m2 | 300 mg twice daily | 2 x 150 mg | --- |
1.17 to 1.33 m2 | 350 mg twice daily | 1 x 50 mg + 2 x 150 mg | --- |
1.34 to 1.51 m2 | 400 mg twice daily | 2 x 50 mg + 2 x 150 mg | 2 x 200 mg |
1.52 to 1.69 m2 | 450 mg twice daily | 3 x 150 mg | 1 x 200 mg + 1 x 250 mg |
1.7 m2 or greater | 500 mg twice daily | 1 x 50 mg + 3 x 150 mg | 2 x 250 mg |
Administration
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- Administer XALKORI capsules or pellets orally, twice daily, with or without food.
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- If a dose of XALKORI capsules or pellets is missed, make up that dose unless the next dose is due within 6 hours.
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- If vomiting occurs after taking a dose of XALKORI capsules or pellets, do not take an additional dose. Take the next dose at the regular scheduled time.
XALKORI Capsules
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- Swallow XALKORI capsules whole, with or without food twice daily.
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- Do not chew, crush or split XALKORI capsules.
XALKORI Pellets
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- XALKORI pellets are supplied encapsulated in shells.
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- Do not chew or crush XALKORI pellets.
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- Do not swallow XALKORI pellets encapsulated in the shell.
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- XALKORI pellets can be administered by 2 options:
- 1.
- Open shell(s) containing XALKORI pellets and empty the contents directly into the patient’s mouth.
- 2.
- Open shell(s) containing XALKORI pellets and empty the contents into a consumer-supplied oral dosing aid (e.g., spoon, medicine cup). Administer XALKORI pellets via the dosing aid directly into the patient’s mouth.
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- Immediately after administration, give a sufficient amount of water to ensure that all medication is swallowed.
Concomitant Treatments for Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT
Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting. Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities.
Consider intravenous or oral hydration for patients at risk of dehydration, and replace electrolytes as clinically indicated [see Warnings and Precautions (5.6)].
Dosage Modifications for Adverse Reactions
The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are provided in Table 4.
Dose Reduction | Dose and Schedule |
First Dose Reduction | 200 mg twice daily |
Second Dose Reduction | 250 mg once daily |
Permanently discontinue XALKORI capsules or pellets if unable to tolerate 250 mg taken once daily. | |
The recommended dosage modifications for adverse reactions for pediatric patients with ALCL or IMT and young adults with ALCL are based on body surface area and are provided in Table 5.
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Body Surface Area (BSA) | First Dose Reduction | Second Dose Reduction * | ||
Dosage | Dosage Form and Strength to Achieve Recommended Dose Reduction | Dosage | Dosage Form and Strength to Achieve Recommended Dose Reduction | |
0.38 to 0.46 m2 | 90 mg twice daily | Pellets: 2 x 20 mg + 1 x 50 mg | 70 mg twice daily | Pellets: 1 x 20 mg + 1 x 50 mg |
0.47 to 0.51 m2 | 100 mg twice daily | Pellets: 2 x 50 mg | 80 mg twice daily | Pellets: 4 x 20 mg |
0.52 to 0.61 m2 | 120 mg twice daily | Pellets: 1 x 20 mg + 2 x 50 mg | 90 mg twice daily | Pellets: 2 x 20 mg + 1 x 50 mg |
0.62 to 0.80 m2 | 150 mg twice daily | Pellets: 1 x 150 mg | 120 mg twice daily | Pellets: 1 x 20 mg + 2 x 50 mg |
0.81 to 0.97 m2 | 200 mg twice daily | Pellets: 1 x 50 mg + 1 x 150 mg | 150 mg twice daily | Pellets: 1 x 150 mg |
0.98 to 1.16 m2 | 220 mg twice daily | Pellets: 1 x 20 mg + 1 x 50 mg + 1 x 150 mg | 170 mg twice daily | Pellets: 1 x 20 mg + 1 x 150 mg |
1.17 to 1.33 m2 | 250 mg twice daily | Pellets: 2 x 50 mg + 1 x 150 mg | 200 mg twice daily | Pellets: 1 x 50 mg + 1 x 150 mg |
1.34 to 1.69 m2 | 250 mg twice daily | Pellets: 2 x 50 mg + 1 x 150 mg Or Capsule: 1 x 250 mg | 200 mg twice daily | Pellets: 1 x 50 mg + 1 x 150 mg Or Capsule: 1 x 200 mg |
1.7 m2 or greater | 400 mg twice daily | Pellets: 2 x 50 mg + 2 x 150 mg Or Capsule: 2 x 200 mg | 250 mg twice daily | Pellets: 2 x 50 mg + 1 x 150 mg Or Capsule: 1 x 250 mg |
Recommended Dosage Modifications for Hematologic Adverse Reactions for Adult Patients with NSCLC or IMT
The recommended dosage modifications for hematologic adverse reactions for adult patients with NSCLC or IMT are provided in Table 6.
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Severity of Adverse Reaction † | XALKORI Dosage Modification |
Grade 3 | Withhold until recovery to Grade 2 or less, then resume at the same dosage. |
Grade 4 | Withhold until recovery to Grade 2 or less, then resume at next lower dosage. |
Monitor complete blood counts including differential weekly for the first month of therapy and then at least monthly, with more frequent monitoring if Grade 3 or 4 abnormalities, fever, or infection occur.
Recommended Dosage Modifications for Hematologic Adverse Reactions in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT
The recommended dosage modifications for hematologic adverse reactions in pediatric and young adult patients with ALCL or pediatric patients with IMT are provided in Table 7.
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Severity of Adverse Reaction | XALKORI Dosage Modification |
Absolute Neutrophil Count (ANC) | |
Less than 0.5 x 109/L | First occurrence: Withhold until recovery to ANC greater than 1.0 x 109/L, then resume at the next lower dosage.
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Platelet Count | |
25 to 50 x 109/L with concurrent bleeding | Withhold until recovery to platelet count greater than 50 x 109/L and bleeding resolves, then resume at the same dosage. |
Less than 25 x 109/L | Withhold until recovery to platelet count greater than 50 x 109/L, then resume at the next lower dosage. Permanently discontinue for recurrence. |
Anemia | |
Hemoglobin less than 8 g/dL | Withhold until recovery to hemoglobin 8 g/dL or more, then resume at the same dosage. |
Life-threatening anemia; urgent intervention indicated. | Withhold until recovery to hemoglobin 8 g/dL or more, then resume at the next lower dosage. Permanently discontinue for recurrence. |
Recommended Dosage Modifications for Non-Hematologic Adverse Reactions
The recommended dosage modifications for non-hematologic adverse reactions are provided in Table 8.
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Severity of Adverse Reaction * | XALKORI Dosage Modification |
Hepatotoxicity [see Warnings and Precautions (5.1)] | |
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN | Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at next lower dosage. |
ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis) | Permanently discontinue. |
Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)] | |
Any grade drug-related interstitial lung disease/pneumonitis | Permanently discontinue. |
QT Interval Prolongation [see Warnings and Precautions (5.3)] | |
QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms (ECGs) | Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage. |
QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia | Permanently discontinue. |
Bradycardia [see Warnings and Precautions (5.4)] | |
Bradycardia † (symptomatic, may be severe and medically significant, medical intervention indicated) | Withhold until recovery to a resting heart rate according to the patient’s age (based on the 2.5th percentile per age-specific norms) as follows:
Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications. |
Bradycardia † (life-threatening consequences, urgent intervention indicated) | Permanently discontinue if no contributing concomitant medication is identified. |
Ocular Toxicity, including Visual Loss [see Warnings and Precautions (5.5)] | |
Visual Symptoms, Grade 1 (mild symptoms) or Grade 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living) | Monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disorders. |
Visual Loss (Grade 3 or 4 Ocular Disorder, marked decrease in vision) | Discontinue during evaluation of severe visual loss. |
Gastrointestinal Toxicity ‡ [see Warnings and Precautions (5.6)] | |
Nausea (Grade 3: inadequate oral intake for more than 3 days, medical intervention required) | Grade 3 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level. § |
Vomiting (Grade 3: more than 6 episodes in 24 hours for more than 3 days, medical intervention required, i.e., tube feeding or hospitalization; Grade 4: life-threatening consequences, urgent intervention indicated) | Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level. § |
Diarrhea (Grade 3: increase of 7 or more stools per day over baseline; incontinence; hospitalization indicated; Grade 4: life-threatening consequences, urgent intervention indicated) | Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level. § |
Dosage Modifications for Moderate and Severe Hepatic Impairment
The recommended dose of XALKORI in patients with moderate hepatic impairment [any aspartate aminotransferase (AST) and total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than or equal to 3 times ULN] is the first dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
The recommended dose of XALKORI in patients with severe hepatic impairment (any AST and total bilirubin greater than 3 times ULN) is the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Dosage and Administration (2.6), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
Dosage Modification for Severe Renal Impairment
The recommended dosage of XALKORI in patients with severe renal impairment [creatinine clearance (CLcr) less than 30 mL/min, calculated using the modified Cockcroft-Gault equation for adult patients and the Schwartz equation for pediatric patients] not requiring dialysis is the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors
Avoid concomitant use of strong CYP3A inhibitors [see Drug Interactions (7.1)]. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to the second dose reduction shown in Table 4 for adult patients with NSCLC or IMT and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.
Capsules:
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- 200 mg: hard gelatin capsule, size 1, white opaque body and pink opaque cap, with "Pfizer" on the cap and "CRZ 200" on the body.
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- 250 mg: hard gelatin capsule, size 0, pink opaque cap and body, with "Pfizer" on the cap and "CRZ 250" on the body.
Oral Pellets:
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- 20 mg: hard gelatin capsule, size 4, white opaque body and light blue opaque cap, printed with black ink “Pfizer” on the cap and “CRZ 20” on the body.
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- 50 mg: hard gelatin capsule, size 3, light gray opaque body and gray opaque cap, printed with black ink “Pfizer” on the cap and “CRZ 50” on the body.
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- 150 mg: hard gelatin capsule, size 0, light blue opaque body and cap, printed with black ink “Pfizer” on the cap and “CRZ 150” on the body.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of XALKORI in pregnant women. In animal reproduction studies, oral administration of crizotinib to pregnant rats during organogenesis at exposures similar to those expected with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at doses ≥50 mg/kg/day (approximately 0.6 times the recommended human dose based on AUC) in rats. No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the recommended human dose based on AUC) or in rabbits at doses of up to 60 mg/kg/day (approximately 1.6 times the recommended human dose based on AUC), though fetal body weights were reduced at these doses.
Lactation
Risk Summary
There is no information regarding the presence of crizotinib or its metabolites in human milk, or the effects on the breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the last dose.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating XALKORI [see Use in Specific Population (8.1)].
Contraception
XALKORI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Females
Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for 45 days after the last dose.
Males
Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for 90 days after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Based on reproductive organ findings in animals, XALKORI may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of XALKORI have been established in pediatric patients 1 year of age and older with relapsed or refractory, systemic ALK-positive ALCL or with unresectable, recurrent, or refractory ALK-positive IMT [see Adverse Reactions (6.1), Clinical Studies (14.2, 14.3)]. The safety and effectiveness have not been established in pediatric patients younger than 1 year of age with ALCL or with IMT, or in any pediatric patients with NSCLC.
In a study that evaluated XALKORI in combination with chemotherapy in pediatric patients with newly diagnosed ALCL (Study ANHL12P1; NCT01979536), 13 of 66 (20%) patients had a Grade 2 or higher thromboembolic event, including pulmonary embolism in 6%. The safety and effectiveness of XALKORI in combination with chemotherapy have not been established in patients with newly diagnosed ALCL.
Juvenile Animal Toxicity Data
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 5.4 times the recommended human dose based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.
Geriatric Use
Of the total number of patients with ALK-positive metastatic NSCLC in clinical studies of XALKORI (n=1669), 16% were 65 years or older and 3.8% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.
Clinical studies of XALKORI in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.
Hepatic Impairment
Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin greater than 1.5 times ULN and less than or equal to 3 times ULN) or severe (any AST and total bilirubin greater than 3 times ULN) hepatic impairment [see Clinical Pharmacology (12.3)]. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.7)]. No dose adjustment is recommended in patients with pre-existing mild hepatic impairment (AST > ULN and total bilirubin less than or equal to 1 times ULN or any AST and total bilirubin greater than 1 times ULN but less than or equal to1.5 times ULN).
Renal Impairment
Increased exposure to crizotinib occurred in patients with pre-existing severe renal impairment (CLcr less than 30 mL/min calculated using the modified Cockcroft-Gault equation for adult patients and the Schwartz equation for pediatric patients) not requiring dialysis, therefore reduce dosage of XALKORI in these patients [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min).
None.
Hepatotoxicity
Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of the 1719 patients treated with XALKORI for NSCLC across clinical trials [see Adverse Reactions (6.1)]. Concurrent elevations in ALT or AST ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in <1% of patients treated with XALKORI. Increased ALT or AST >5 times the ULN occurred in 11% and 6% of patients, respectively. One percent (1.0%) of patients required permanent discontinuation due to elevated transaminases. Increased transaminases generally occurred within the first 2 months of treatment.
In Study ADVL0912, of 121 patients ages 1 to ≤21 years treated with XALKORI for relapsed or refractory tumors including ALCL and IMT, 71% and 79% had increases of AST and ALT, respectively, with increased ALT or AST >5 times the ULN in 6% each. Of the 26 patients with ALCL treated with XALKORI, 65% and 81% had increases of AST and ALT, respectively, with increases >5 times the ULN in 4% each. Of the 14 pediatric patients with IMT treated with XALKORI, 71% had increases of AST and 71% had increases of ALT.
In Study A8081013, of the 7 adult patients with IMT treated with XALKORI, 57% and 43% had increases of AST and ALT, respectively.
Monitor 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 increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases. Withhold, reduce dose, or permanently discontinue XALKORI for hepatotoxicity as recommended [see Dosage and Administration (2.6)].
Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC (n=1719), 2.9% of XALKORI-treated patients had ILD of any grade, 1% had Grade 3 or 4 ILD, and 0.5% had fatal ILD [see Adverse Reactions (6.1)]. Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI.
In Study ADVL0912, among 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including ALCL and IMT, ILD occurred in 0.8% of patients.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.6)].
QT Interval Prolongation
QTc prolongation can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC, 2.1% of 1616 patients had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 500 ms and 5% of 1582 patients had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECGs.
In Study ADVL0912, QTc prolongation was reported as an adverse reaction in 4.1% of patients, including 8% of patients with ALCL and 7% of pediatric patients with IMT.
Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Withhold, reduce dose, or permanently discontinue XALKORI for QT/QTc interval prolongation as recommended [see Dosage and Administration (2.6), Clinical Pharmacology (12.2)].
Bradycardia
Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials in patients with NSCLC, bradycardia occurred in 13% of 1719 patients treated with XALKORI. Grade 3 syncope occurred in 2.4% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients [see Adverse Reactions (6.1)].
In Study ADVL0912, among 121 patients ages 1 to ≤21 years treated with XALKORI, bradycardia was reported in 14%, including Grade 3 bradycardia in 0.8% of patients. Of the 26 patients with ALCL treated with XALKORI, bradycardia (all Grade 1) was reported in 19%. Of the 14 pediatric patients with IMT treated with XALKORI, bradycardia was reported in 14% of patients, including Grade 3 bradycardia in 7% of patients.
Avoid using XALKORI in combination with other medications known to cause bradycardia (e.g., beta-blockers, nondihydropyridine-calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. Withhold, reduce dose, or permanently discontinue XALKORI for bradycardia as recommended [see Dosage and Administration (2.6)].
Severe Visual Loss
Across all clinical trials in patients with NSCLC, the incidence of Grade 4 visual field defect with visual loss was 0.2% of 1719 patients [see Adverse Reactions (6.1)]. Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss.
In Study ADVL0912, visual disorders occurred in 46% of 121 patients with XALKORI, including 65% of 26 patients with ALCL and 50% of 14 patients with IMT. Of the 56 patients who experienced visual disorders, one pediatric patient with IMT experienced Grade 3 myopic optic nerve disorder. The most common visual symptoms were blurred vision and visual impairment.
Assessment of visual symptoms for all patients is recommended monthly during treatment. Report new visual symptoms to an eye specialist.
For pediatric and young adult patients with ALCL or pediatric patients with IMT, obtain baseline and follow-up ophthalmologic examinations including retinal examination within 1 month of starting XALKORI and every 3 months thereafter. The ophthalmological evaluation should consist of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate [see Dosage and Administration (2.6), Adverse Reactions (6.1)].
Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified [see Dosage and Administration (2.6)]. There is insufficient information to characterize the risks of resumption of XALKORI in patients who develop visual symptoms or visual loss. A decision to resume XALKORI should consider the potential benefits versus risks to the patient.
Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT
XALKORI can cause severe gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT [see Adverse Reactions (6.1)]. In patients with ALCL (n=26), gastrointestinal toxicity occurred in 100% of patients; Grade 3 gastrointestinal toxicity occurred in 27% of patients and included diarrhea, nausea, vomiting, and stomatitis. In pediatric patients with IMT (n=14), vomiting occurred in 93%, nausea occurred in 86%, and diarrhea occurred in 64% of patients.
Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT. Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting. If patients develop Grade 3 nausea lasting 3 days or Grade 3 or 4 diarrhea or vomiting despite maximum medical therapy, withhold XALKORI until resolved, and then resume at the next lower dose level. Consider supportive care such as hydration, electrolyte supplementation, and nutritional support as clinically indicated [see Dosage and Administration (2.6)].
Embryo-Fetal Toxicity
Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for 45 days following the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for 90 days after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].