Xalkori (CRIZOTINIB) capsule
Pfizer Laboratories Div Pfizer Inc

Pfizer Laboratories Div Pfizer Inc
Pfizer Inc
Pfizer Ireland Pharmaceuticals
Pfizer Manufacturing Deutschland GmbH
Upjohn Manufacturing Ireland Unlimited Company
Pfizer Asia Manufacturing Pte Ltd
Xalkori
CRIZOTINIB
CRIZOTINIB
CRIZOTINIB
SILICON DIOXIDE
MICROCRYSTALLINE CELLULOSE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
MAGNESIUM STEARATE
GELATIN, UNSPECIFIED
TITANIUM DIOXIDE
FERRIC OXIDE RED
SHELLAC
PROPYLENE GLYCOL
AMMONIA
POTASSIUM HYDROXIDE
FERROSOFERRIC OXIDE
SODIUM STARCH GLYCOLATE TYPE A
opaque
Pfizer;CRZ;250
Xalkori
CRIZOTINIB
CRIZOTINIB
CRIZOTINIB
SILICON DIOXIDE
MICROCRYSTALLINE CELLULOSE
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
MAGNESIUM STEARATE
GELATIN, UNSPECIFIED
FERRIC OXIDE RED
TITANIUM DIOXIDE
SHELLAC
PROPYLENE GLYCOL
AMMONIA
POTASSIUM HYDROXIDE
FERROSOFERRIC OXIDE
SODIUM STARCH GLYCOLATE TYPE A
cap
body
Pfizer;CRZ;200
Xalkori
CRIZOTINIB
CRIZOTINIB
CRIZOTINIB
GELATIN, UNSPECIFIED
TITANIUM DIOXIDE
STEARYL ALCOHOL
POLOXAMER 407
SUCROSE
TALC
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
GLYCERYL MONOSTEARATE
MEDIUM-CHAIN TRIGLYCERIDES
FD&C BLUE NO. 1
light blue cap
light blue body
Pfizer;CRZ;150
Xalkori
CRIZOTINIB
CRIZOTINIB
CRIZOTINIB
GELATIN, UNSPECIFIED
TITANIUM DIOXIDE
STEARYL ALCOHOL
POLOXAMER 407
SUCROSE
TALC
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
GLYCERYL MONOSTEARATE
MEDIUM-CHAIN TRIGLYCERIDES
FERROSOFERRIC OXIDE
cap
light gray body
Pfizer;CRZ;50
Xalkori
CRIZOTINIB
CRIZOTINIB
CRIZOTINIB
STEARYL ALCOHOL
POLOXAMER 407
SUCROSE
TALC
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
GLYCERYL MONOSTEARATE
MEDIUM-CHAIN TRIGLYCERIDES
GELATIN, UNSPECIFIED
TITANIUM DIOXIDE
FD&C BLUE NO. 1
light blue cap
body
Pfizer;CRZ;20

Dosage and Administration (2)

9/2023

1 INDICATIONS AND USAGE

XALKORI is a kinase inhibitor 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. (1.1, 2.1)
  • 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. (1.2, 2.3)
    • oLimitations of Use: The safety and efficacy of XALKORI have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.
  • adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. (1.3, 2.3)

1.1 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)].

1.2 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.

1.3 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.

2 DOSAGE AND ADMINISTRATION

        

  • Metastatic NSCLC: The recommended dosage is 250 mg orally twice daily. (2.3)
  • Systemic ALCL: The recommended dosage is 280 mg/m2 orally twice daily based on body surface area. (2.3)
  • Unresectable IMT:
    • oAdult: The recommended dosage is 250 mg orally twice daily. (2.3)
    • oPediatric: The recommended dosage is 280 mg/m2 orally twice daily based on body surface area. (2.3)
  • See full prescribing information for dosage adjustments by indication for patients with moderate or severe hepatic impairment or severe renal impairment. (2.7, 2.8)

2.1 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.

2.2 Recommended Testing During Treatment with XALKORI

  • 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)].
  • 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)].
  • 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)].

2.3 Recommended Dosage

The recommended dosage of XALKORI is provided in Table 1.

Table 1. Recommended Dosage of XALKORI

Indication

Recommended Dosage of XALKORI

ALK- or ROS1-Positive Metastatic NSCLC

Adults:
250 mg orally twice daily

Relapsed or Refractory, Systemic ALK-Positive ALCL

Pediatric Patients and Young Adults:
280 mg/m2 orally twice dailySee Table 2 for Recommended Dosage based on body surface area for pediatric patients and young adults with ALCL for the capsules and oral pellets.

Unresectable, Recurrent, or Refractory ALK-Positive IMT

Adults:
250 mg orally twice daily

Pediatric Patients:
280 mg/m2 orally twice dailySee Table 3 for Recommended Dosage based on body surface area for pediatric patients with IMT for the capsules and oral pellets.

Recommended Dosage for Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC

  • 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.
  • 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

  • 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.
  • 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.

Table 2. Recommended XALKORI Dosage for Pediatric Patients 1 Year of Age and Older and Young Adults With ALK-Positive ALCL Using Either XALKORI Capsules or Pellets

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer No more than 4 oral pellet shells are to be used for a single dose.

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

  • The recommended dosage for adult patients with unresectable, recurrent, or refractory ALK-positive IMT is provided in Table 1.
  • 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.
  • 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.

Table 3. Recommended XALKORI Dosage for Pediatric Patients 1 Year of Age and Older with ALK-positive IMT Using Either XALKORI Capsules or Pellets

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer No more than 4 oral pellet shells are to be used for a single dose.

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

2.4 Administration

  • Administer XALKORI capsules or pellets orally, twice daily, with or without food.
  • If a dose of XALKORI capsules or pellets is missed, make up that dose unless the next dose is due within 6 hours.
  • 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

  • Swallow XALKORI capsules whole, with or without food twice daily.
  • Do not chew, crush or split XALKORI capsules.

XALKORI Pellets

  • XALKORI pellets are supplied encapsulated in shells.
  • Do not chew or crush XALKORI pellets.
  • Do not swallow XALKORI pellets encapsulated in the shell.
  • 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.
  • Immediately after administration, give a sufficient amount of water to ensure that all medication is swallowed.

2.5 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)].

2.6 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are provided in Table 4.

Table 4. Recommended Dosage Reductions for Adverse Reactions for Adult Patients with NSCLC or IMT Using XALKORI Capsules or Pellets

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.

Table 5. Recommended Dosage Reductions for Adverse Reactions for Pediatric Patients with ALCL or IMT and Young Adults with ALCL Using XALKORI Capsules or Pellets

Body Surface Area

(BSA)

First Dose Reduction

Second Dose Reduction Permanently discontinue in patients who are unable to tolerate XALKORI capsules or pellets after 2 dose reductions.

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.

Table 6. Adult Patients with NSCLC or IMT: XALKORI Dosage Modification – Hematologic ToxicitiesExcept lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Severity of Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

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.

Table 7. Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI Dosage Modification for Hematologic Adverse Reactions

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.

Second occurrence:

  • Permanently discontinue for recurrence complicated by febrile neutropenia or infection.
  • For uncomplicated Grade 4 neutropenia, either permanently discontinue, or withhold until recovery to ANC greater than 1.0 x 109/L, then resume at the next lower dosage.Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

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.

Table 8. All Patients: XALKORI Dosage Modification for Non-Hematologic Adverse Reactions

Severity of Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

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)]

BradycardiaAdult patients: Heart rate less than 60 beats per minute (bpm); Pediatric patients: Resting heart rate less than the 2.5th percentile per age-specific norms. (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:

  • 1 to less than 2 years: 91 bpm or above
  • 2 to 3 years: 82 bpm or above
  • 4 to 5 years: 72 bpm or above
  • 6 to 8 years: 64 bpm or above
  • Older than 8 years: 60 bpm or above

Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications.

If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to the age-specific heart rate provided above.

If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose adjusted, resume at reduced dose upon recovery to asymptomatic bradycardia or to the age-specific heart rate provided above.

Bradycardia

(life-threatening consequences, urgent intervention indicated)

Permanently discontinue if no contributing concomitant medication is identified.

If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at the second dose reduction level in Table 4 or 5 upon recovery to asymptomatic bradycardia or to the heart rate criteria listed for management of symptomatic or severe, medically significant bradycardia, with frequent monitoring.

Permanently discontinue for recurrence.

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.

Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss if no other cause found on evaluation.

Gastrointestinal Toxicity Dosage modifications for gastrointestinal toxicity for pediatric patients with ALCL or IMT and young adults with ALCL only. [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.Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

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.

2.7 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)].

2.8 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)].

2.9 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.

3 DOSAGE FORMS AND STRENGTHS

Capsules:

  • 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.
  • 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:

  • 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.
  • 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.
  • 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.

Capsules: 200 mg, 250 mg (3)

Oral pellets: 20 mg, 50 mg, 150 mg (3)

4 CONTRAINDICATIONS

None.

None. (4)

5 WARNINGS AND PRECAUTIONS

  • Hepatotoxicity: Fatal hepatotoxicity has occurred. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (2.2, 2.6, 5.1)
  • Interstitial Lung Disease (ILD)/Pneumonitis: Permanently discontinue in patients with ILD/pneumonitis. (2.6, 5.2)
  • QT Interval Prolongation: Monitor electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (2.6, 5.3)
  • Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (2.6, 5.4)
  • Severe Visual Loss: XALKORI can cause visual changes including severe visual loss. Monitor and evaluate for ocular toxicity throughout treatment. Discontinue XALKORI in patients with severe visual loss. (2.2, 2.6, 5.5)
  • Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI can cause severe nausea, vomiting, diarrhea, and stomatitis. Provide standard antiemetic and antidiarrheal agents. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (2.6, 5.6)
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.7, 8.1, 8.3)

5.1 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)].

5.2 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)].

5.3 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)].

5.4 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)].

5.5 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.

5.6 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)].

5.7 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)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

The most common adverse reactions (≥25%) in adult patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. (6.1)

The most common adverse reactions (≥35%) in patients with ALCL are diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus. Grade 3–4 laboratory abnormalities (≥15%) are neutropenia, lymphopenia, and thrombocytopenia. (6.1)

The most common adverse reactions (≥35%) in adult patients with IMT are vision disorders, nausea, and edema. (6.1)

The most common adverse reactions (≥35%) in pediatric patients with IMT are vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data in the Warnings and Precautions reflect exposure to XALKORI in 1719 patients with NSCLC who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single-arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154). The data also reflect exposure to XALKORI in 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including 26 patients with systemic ALCL and 14 pediatric patients with IMT, in a single-arm trial (Study ADVL0912). The data are also described for 7 adult patients with IMT treated with XALKORI in a single-arm trial (Study A8081013).

ALK- or ROS1-Positive Metastatic NSCLC

The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg orally twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3).

The most common adverse reactions (≥25%) of XALKORI in patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 (PROFILE 1014)

The data in Table 9 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 169 patients in the chemotherapy arm received pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg×min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.

The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.

Serious adverse events were reported in 34% of patients treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis.

Dose reductions due to adverse reactions were required in 6% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%).

Permanent discontinuation of XALKORI treatment for adverse reactions was 8%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%).

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 9. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3–4) with XALKORI than Chemotherapy in Study 1Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
Adverse Reaction XALKORI
(N=171)
Chemotherapy
(Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)
(N=169)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)

Cardiac

  BradycardiaBradycardia (Bradycardia, Sinus bradycardia).

14

1

1

0

  Electrocardiogram QT prolonged

6

2

2

0

Eye

  Vision disorderVision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment).

71

1

10

0

Gastrointestinal

  Diarrhea

61

2

13

1

  Vomiting

46

2

36

3

  Constipation

43

2

30

0

  Abdominal painAbdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness).

26

0

12

0

  Dyspepsia

14

0

2

0

  Dysphagia

10

1

2

1

  EsophagitisEsophagitis (Esophagitis, Esophageal ulcer).

6

2

1

0

General

  EdemaEdema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema).

49

1

12

1

  Pyrexia

19

0

11

1

Infections

  Upper respiratory infectionUpper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).

32

0

12

1

Investigations

  Increased weight

8

1

2

0

Musculoskeletal and Connective Tissue

  Pain in extremity

16

0

7

0

  Muscle spasm

8

0

2

1

Nervous System

  Dysgeusia

26

0

5

0

  Headache

22

1

15

0

  DizzinessDizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope).

18

0

10

1

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), syncope (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%).

Table 10. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 1
XALKORI Chemotherapy
Laboratory Abnormality Any Grade
(%)
Grade 3–4
(%)
Any Grade
(%)
Grade 3–4
(%)
Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 99%; Grade 3: 2%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 92%; Grade 3: 0%; Grade 4: 1%).

Hematology

  Neutropenia

52

11

59

16

  Lymphopenia

48

7

53

13

Chemistry

  Increased ALT

79

15

33

2

  Increased AST

66

8

28

1

  Hypophosphatemia

32

10

21

6

Previously Treated ALK-Positive Metastatic NSCLC - Study 2 (PROFILE 1007)

The data in Table 11 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion every 3 weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.

The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.

Serious adverse reactions were reported in 37% of patients treated with XALKORI and 23% of patients in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 5% of patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis.

Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were increased ALT (8%) including some patients with concurrent increased AST, QTc prolongation (2.9%), and neutropenia (2.3%).

XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), increased ALT and AST (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).

Tables 11 and 12 summarize common adverse reactions and laboratory abnormalities, respectively, in XALKORI-treated patients.

Table 11. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3–4) with XALKORI than Chemotherapy in Study 2Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:

Adverse Reaction

XALKORI
(N=172)

Chemotherapy
(Pemetrexed or Docetaxel)
(N=171)

All Grades
(%)

Grade 3–4
(%)

All Grades
(%)

Grade 3–4
(%)

Nervous System

  Dysgeusia

26

0

9

0

  DizzinessDizziness (Balance disorder, Dizziness, Postural dizziness).

22

1

8

0

  Syncope

3

3

0

0

Eye

  Vision disorderVision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters).

60

0

9

0

Cardiac

  Electrocardiogram QT prolonged

5

3

0

0

  BradycardiaBradycardia (Bradycardia, Sinus bradycardia).

5

0

0

0

Investigations

  Decreased weight

10

1

4

0

Gastrointestinal

  Diarrhea

60

0

19

1

  Nausea

55

1

37

1

  Vomiting

47

1

18

0

  Constipation

42

2

23

0

  Dyspepsia

8

0

3

0

Infections

  Upper respiratory infectionUpper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).

26

0

13

1

Respiratory, Thoracic and Mediastinal

  Pulmonary embolismPulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism).

6

5

2

2

General

  EdemaEdema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema).

31

0

16

0

Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.4%).

Table 12. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 2
Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 96%; Grade 3: 1%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 72%; Grade 3: 0%; Grade 4: 0%).

XALKORI

Chemotherapy

Laboratory Abnormality

Any Grade
(%)

Grade 3–4
(%)

Any Grade
(%)

Grade 3–4
(%)

Hematology

  Lymphopenia

51

9

60

25

  Neutropenia

49

12

28

12

Chemistry

  Increased ALT

76

17

38

4

  Increased AST

61

9

33

0

  Hypophosphatemia

28

5

25

6

  Hypokalemia

18

4

10

1

ROS1-Positive Metastatic NSCLC - Study 3 (PROFILE 1001)

The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months.

Description of Selected Adverse Reactions in Patients with Metastatic NSCLC

Vision disorders: Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 0.8% of patients with Grade 3 and 0.2% of patients with Grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 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 1 and 2 (>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.

Neuropathy: Neuropathy, most commonly sensory in nature, occurred in 25% of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity.

Renal cysts: Renal cysts were experienced by 3.0% of 1719 patients. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.

Renal toxicity: The estimated glomerular filtration rate (eGFR) decreased from a baseline median of 96.42 mL/min/1.73 m2 (n=1681) to a median of 80.23 mL/min/1.73 m2 at 2 weeks (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m2) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m2, 38% had a decrease to eGFR to <60 mL/min/1.73 m2, and 3.6% had a decrease to eGFR to <30 mL/min/1.73 m2.

Relapsed or Refractory, Systemic ALK-Positive ALCL - Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies 14.2], which included 26 patients with relapsed or refractory, systemic ALCL after at least one systemic therapy. Eligible patients were 1 to ≤21 years of age and were required to have an absolute neutrophil count ≥1000/mm3 (750/mm3 if bone marrow was involved), platelet count ≥75,000/mm3 (25,000/mm3 if bone marrow was involved), creatinine clearance ≥70ml/min/1.73m2, and QTc ≤480 msec. The study excluded patients with ALT >2.5 times upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and central nervous system tumors.

Patients with ALCL received XALKORI 165 mg/m2 or 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure was 5.4 months (range 1.8, 82.3 months), with 46% of patients treated for at least 6 months and 35% of patients treated for at least 12 months.

Serious adverse reactions occurred in 35% of patients with ALCL treated with XALKORI. The most frequent serious adverse reactions were neutropenia (12%) and hypotension (8%).

Dose interruptions and dose reductions occurred in 77% and 19% of patients with ALCL, respectively. XALKORI was discontinued for an adverse reaction in 8% of patients.

The most common adverse reactions (≥35%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritis.

The most common Grade 3 or 4 laboratory abnormalities (≥15%) included neutropenia, lymphopenia, and thrombocytopenia. Grade 4 laboratory abnormalities (≥15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%).

Selected adverse reactions are summarized in Table 13.

Table 13. Adverse Reactions in ≥20% of Patients with Systemic ALCL in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.

Adverse Reaction

XALKORI
N=26

All Grades
(%)

Grade 3–4
(%)

Blood and Lymphatic System Disorders Derived from laboratory values collected in Cycle 1 and adverse reaction data.

  NeutropeniaIncludes neutrophil count decreased.

100

77

  LymphopeniaIncludes lymphocyte count decreased.

58

38

  Anemia

54

3.8

  ThrombocytopeniaIncludes platelet count decreased.

38

19

Gastrointestinal Disorders

  Diarrhea

92

12

  Vomiting

92

3.8

  Nausea

77

3.8

  Abdominal Pain

50

0

  StomatitisIncludes oral pain, oropharyngeal pain, stomatitis.

46

8

  Constipation

31

0

Renal Disorders

  Blood creatinine increased

100

0

Investigations

  ALT increased

81

3.8

  AST increased

65

3.8

  Hypocalcemia

62

3.8

  Hypoalbuminemia

54

0

  Hyperglycemia

46

0

  Hypomagnesemia

46

0

  Hypoglycemia

35

0

  Hypokalemia

31

3.8

  Hypermagnesemia

27

0

  Hyperkalemia

23

0

Nervous System Disorders

  Headache

58

3.8

  Dysgeusia

23

0

  Dizziness

23

0

Eye Disorders

  Vision disordersIncludes blurred vision, visual impairment, photophobia, photopsia, reduced visual acuity, vitreous floaters, cyanopsia, heterophoria, visual field defect.

65

0

Musculoskeletal Disorders

  Musculoskeletal painIncludes arthralgia, back pain, myalgia, non-cardiac chest pain, pain in extremity.

58

12

General Disorders

  Fatigue

46

0

  Pyrexia

38

0

  EdemaIncludes peripheral edema, face edema, periorbital edema, localized edema.

27

0

  Chills

23

0

Metabolism and Nutrition Disorders

  Decreased appetite

42

0

Skin and Subcutaneous Disorders

  Pruritus

35

0

  RashIncludes rash maculopapular, rash pustular.

23

0

Infections

  Upper respiratory tract infectionIncludes upper respiratory tract infection, pharyngitis, rhinitis, sinusitis.

31

0

Respiratory Disorders

  Cough

35

0

  Rhinitis allergic

23

0

Vascular Disorders

  Hypertension

31

0

Clinically relevant adverse reactions in <20% of patients treated with XALKORI included:

  • Cardiac disorders: Bradycardia (19%), electrocardiogram QT prolonged (8%)
  • Vascular disorders: Hypotension (19%)
  • Investigations: Alkaline phosphatase increase (19%), hypernatremia (19%), GGT increase (8%), hyponatremia (12%), hyperuricemia (12%), hypophosphatemia (12%)
  • Nervous system disorders: Peripheral neuropathy (12%)
  • Gastrointestinal disorders: Esophagitis (8%)
  • Blood and lymphatic disorders: Febrile neutropenia (3.8%)
  • Musculoskeletal disorders: Muscular weakness (8%)
  • Renal disorders: Acute renal injury (8%)

Unresectable, Recurrent, or Refractory ALK-Positive IMT

Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies (14.3)] that included 14 pediatric patients with unresectable, recurrent, or refractory IMT.

Pediatric patients with IMT received XALKORI 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. Two patients received a lower dose. The median duration of treatment with XALKORI was 20.5 months.

Serious adverse reactions occurred in 7% of pediatric patients with IMT treated with XALKORI. The most frequent serious adverse reaction was neutropenia and hypotension (7% for each).

Dose interruptions due to an adverse reaction occurred in 71% of patients. Dose reductions due to an adverse reaction occurred in 29% of patients. Permanent discontinuation occurred in 29% of patients.

The most common adverse reactions (≥35%) were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache.

The most common Grade 3 or 4 laboratory abnormality (>15%) was neutropenia.

Table 14 and Table 15 summarize the adverse reactions and laboratory abnormalities, respectively, in Study ADVL0912.

Table 14. Adverse Reactions in ≥20% of Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.

Adverse Reaction

XALKORI
N=14

All Grades
(%)

Grade 3–4
(%)

Gastrointestinal Disorders

  Vomiting

93

0

  Nausea

86

0

  Diarrhea

64

7

  Abdominal painIncludes abdominal pain and abdominal pain upper.

57

0

  Constipation

36

0

  StomatitisIncludes oral pain and oropharyngeal pain.

29

0

Infections

  Upper respiratory tract infectionIncludes upper respiratory tract infection, pharyngitis, rhinitis.

64

0

  Skin Infection

29

0

Respiratory Disorders

  CoughIncludes cough and productive cough.

64

0

  Rhinitis allergic

29

0

Skin and Subcutaneous Disorders

  RashIncludes rash maculopapular, rash pustular, dermatitis acneiform.

57

0

General Disorders

  Pyrexia

50

0

  Fatigue

43

0

  EdemaIncludes face edema, localized edema, periorbital edema, peripheral edema.

36

7

  PainIncludes pain, bone pain, ear pain.

29

0

Eye Disorders

  Vision disordersIncludes photophobia, photopsia, vision blurred, visual impairment, vitreous floaters.

50

0

Musculoskeletal Disorders

  Musculoskeletal painIncludes arthralgia, myalgia, non-cardiac chest pain, pain in extremity.

43

0

Nervous System Disorders

  Headache

36

0

Metabolism and Nutrition Disorders

  Decreased appetite

29

0

Vascular Disorders

  Hypotension

21

7

Clinically relevant adverse reactions in <20% of pediatric patients with IMT treated with XALKORI included:

Cardiac disorders: Bradycardia (14%), electrocardiogram QT prolonged (7%)

Gastrointestinal disorders: Dyspepsia (14%), esophagitis (7%)

Vascular disorders: Hypertension (14%)

Nervous system disorders: Peripheral neuropathy (7%)

Blood and lymphatic disorders: Febrile neutropenia (7%)

Musculoskeletal disorders: Muscular weakness (7%)

Table 15. Laboratory Abnormalities (≥15%) That Worsened from Baseline in Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912

Laboratory Abnormality

XALKORI The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement and varied from 13 to 14. , Laboratory abnormality data were only collected for the 1st cycle (28 days) of treatment for the duration of the study.

Any Grade
(%)

Grade 3–4
(%)

Chemistry

  Increased creatinine

100

0

  Decreased calcium

36

0

  Increased magnesium

23

0

  Decreased phosphate

15

0

Hematology

  Decreased neutrophils

64

36

Hepatic

  Increased ALT

36

0

Study A8081013

The safety of XALKORI for adult patients with ALK-positive IMT was evaluated in Study A8081013 [see Clinical Studies (14.3)] that included 7 patients with IMT with a median age of 38 years (range 23 to 73). The safety profile of this patient group was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive or ROS1-positive NSCLC.

The most frequent adverse reactions (≥20%) were vision disorders, nausea, and edema.

6.2 Postmarketing Experience

The following additional adverse reaction has been identified during post-approval use of XALKORI. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Investigations: Increased blood creatine phosphokinase

7 DRUG INTERACTIONS

  • Strong CYP3A Inhibitors: Avoid concomitant use. (2.9, 7.1)
  • Strong CYP3A Inducers: Avoid concomitant use. (7.1)
  • CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious adverse reactions. (7.2)

7.1 Effect of Other Drugs on XALKORI

Strong or Moderate CYP3A Inhibitors

Concomitant use of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions of XALKORI. Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the XALKORI dosage [see Dosage and Administration (2.9)]. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Use caution with concomitant use of moderate CYP3A inhibitors.

Strong CYP3A Inducers

Concomitant use of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease the efficacy of XALKORI. Avoid concomitant use of strong CYP3A inducers.

7.2 Effect of XALKORI on Other Drugs

CYP3A Substrates

Concomitant use of crizotinib increases plasma concentrations of CYP3A substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions of these substrates. Avoid concomitant use of XALKORI with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling.

7.3 Drugs That Prolong the QT Interval

XALKORI can prolong the QT/QTc interval. Avoid concomitant use of XALKORI with drugs that prolong the QT interval [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)].

7.4 Drugs That Cause Bradycardia

XALKORI can cause bradycardia. Avoid concomitant use of XALKORI with drugs that cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) [see Warnings and Precautions (5.4)].

8 USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed. (8.2)

8.1 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.

8.2 Lactation