Drug Safety-related Labeling Changes (SrLC)

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XALKORI (NDA-202570)

(CRIZOTINIB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/07/2023 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Severe Visual Loss

Additions and/or revisions underlined:

…

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)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Dosage and Administration

…

Capsules:

Advise patients to swallow XALKORI capsules whole [see Dosage and Administration (2.4)].

Oral Pellets:

Inform patient or caregiver to open the encapsulated XALKORI oral pellets and administer the oral pellets directly in the patient’s mouth or with a consumer-supplied oral dosing aid, for example a spoon or medicine cup. Advise patient or caregiver that the oral pellets are not to be chewed and to give a sufficient amount of water after pellets are administered to ensure all oral pellets are swallowed [see Dosage and Administration (2.4)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

XALKORI is a prescription medicine that is used to treat:

• adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body and is caused by a defect in either a gene called ALK (anaplastic lymphoma kinase) or a gene called ROS1.

• children 1 year of age and older and young adults with ALCL when your ALCL with a defect in a gene called ALK has returned or you have tried a treatment and it did not work or is no longer working.

  • It is not known if XALKORI is safe and effective in older adults with ALCL.

• adults and children 1 year of age and older with IMT when your IMT with a defect in a gene called ALK cannot be removed by surgery, has returned, or you have tried a treatment and it did not work or is no longer working.

  It is not known if XALKORI is safe and effective in children younger than 1 year of age with ALCL or IMT, or in any children with NSCLC.

  …

  How should I take XALKORI?

• Take XALKORI exactly as prescribed by your healthcare provider.

  XALKORI comes as capsules and oral pellets.

• If your healthcare provider prescribes XALKORI capsules:

  • Swallow XALKORI capsules whole. Do not chew, crush or split XALKORI capsules.

  • Take XALKORI capsules with or without food.

     

• If your healthcare provider prescribes XALKORI oral pellets:

  • See the Instructions for Use at the end of this Medication Guide for instructions about the right way to prepare and give or take XALKORI oral pellets.

  • XALKORI oral pellets should be poured from the shell(s) directly into the mouth, or given or taken with a spoon or medicine cup. Right after giving or taking the oral pellets, give or drink enough water to make sure all oral pellets are swallowed.

  • Do not swallow shells containing XALKORI oral pellets.

  • Do not chew or crush the XALKORI oral pellets.

  • Take XALKORI oral pellets with or without food.

     

• Your healthcare provider will check your blood cell counts weekly during the first month of treatment with XALKORI and then at least monthly during treatment.

  …

  What are the ingredients in XALKORI?

  Active ingredient: crizotinib

  …

  Oral pellets inactive ingredients: The uncoated pellets contain poloxamer and stearyl alcohol. The film-coating contains hypromellose, glyceryl monostearate, medium chain triglycerides, polyethylene glycol/macrogol, sucrose, and

  talc.

07/14/2022 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hepatotoxicity

Additions and/or revisions underlined:

…

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.

…

5.2 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

…

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.

…

5.3 QT Interval Prolongation

Additions and/or revisions underlined:

…

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.

…

5.4 Bradycardia

Additions and/or revisions underlined:

…

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.

…

5.5 Severe Visual Loss

Additions and/or revisions underlined:

…

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 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 (2.4), 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 (2.4)]. 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

Subsection title revised; Additions and/or revisions underlined:

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 (2.4)].

6 Adverse Reactions

Additions and/or revisions underlined:

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

• Hepatotoxicity [see Warnings and Precautions (5.1)]

• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]

• QT Interval Prolongation [see Warnings and Precautions (5.3)]

• Bradycardia [see Warnings and Precautions (5.4)]

• Severe Visual Loss [see Warnings and Precautions (5.5)]

• Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

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.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

Inform patients with ALCL or pediatric patients with IMT of the risk of severe nausea, vomiting, diarrhea, and stomatitis. Advise patients to immediately inform their healthcare provider of problems with swallowing, vomiting, or diarrhea [see Warnings and Precautions (5.6)].

…

09/22/2021 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

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

…

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

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

What should I avoid while taking XALKORI?

• Do not drink grapefruit juice, eat grapefruit or take supplements containing grapefruit extract during treatment with XALKORI. These may increase the amount of XALKORI in the blood.

• XALKORI can cause changes in vision, dizziness, and tiredness. Do not drive or operate machinery if you have any of these symptoms.

• Avoid spending prolonged time in sunlight. XALKORI can make your skin sensitive to the sun (photosensitivity), and you may burn more easily. You should use sunscreen and wear protective clothing that covers your skin to help protect against sunburn if you have to be in the sunlight during treatment with XALKORI.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Photosensitivity

Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure and to use sunscreen or protective clothing during treatment with XALKORI [see Adverse Reactions (6.1)].

…

01/14/2021 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hepatoxicity

Additions and/or revisions underlined:

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 greater than or equal to 3 times the ULN and total bilirubin greater than or equal to 2 times the ULN, with normal alkaline phosphatase, occurred inn <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 less than or equal to21 years treated with XALKORI for relapsed or refractory tumors including ALCL, 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.

Monitor liver function tests, including ALT, AST, and total bilirubin …

5.2 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

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 less than or equal to21 years with relapsed or refractory tumors, including ALCL, ILD occurred in 0.8% of patients.

Monitor patients for pulmonary symptoms …

5.3 QT Interval Prolongation

Additions and/or revisions underlined:

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.

Avoid use of XALKORI in patients with congenital …

5.4 Bradycardia

Additions and/or revisions underlined:

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 less than or equal to21 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%.

Avoid using XALKORI in combination …

5.5 Severe Visual Loss

Additions and/or revisions underlined:

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. Of the 56 patients who experienced visual disorders, one patient experienced Grade 3 optic nerve disorder. The most common visual symptoms were blurred vision and visual impairment.

For patients with ALCL, obtain baseline ophthalmologic examination prior to starting XALKORI. Follow-up ophthalmologic examination including retinal examination is recommended within 1 month of starting XALKORI, every 3 months thereafter, and upon any new visual symptoms. Assessment of visual symptoms is recommended monthly during treatment. Report any visual symptoms to an eye specialist. Withhold XALKORI pending evaluation for any Grade 3 or 4 ocular disorders, and permanently discontinue XALKORI for Grade 3 or 4 ocular disorders unless another cause is identified [see Dosage and Administration (2.5)].

Discontinue XALKORI in any patient with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate for new onset of visual loss and for other visual symptoms as clinically warranted [see Dosage and Administration (2.5), Adverse Reactions (6.1)].

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.

Newly added subsection:

5.6 Gastrointestinal Toxicity in Patients with ALCL

XALKORI can cause severe gastrointestinal toxicities in patients with ALCL [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.

Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities in patients with ALCL. 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 (2.5)].

6 Adverse Reactions

Newly added to the bulleted line listing:

• Gastrointestinal Toxicity in Patients with ALCL [see Warnings and Precautions (5.6)]

  6.1 Clinical Trials Experience

  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 less than or equal to21 years with relapsed or refractory tumors, including 26 patients with systemic ALCL, in a single-arm trial (Study ADVL0912).

  ALK- or ROS1-Positive Metastatic NSCLC

  The data described below is based primarily on 343 patients … NSCLC from a single-arm study (Study 3).

  The most common adverse reactions (greater than or equal to 25%) of XALKORI in patients with NSCLC are vision disorders, nausea …

  The following bolded words have been added:

Description of Selected Adverse Reactions in Patients with Metastatic NSCLC

Vision disorders: Vision disorders, most commonly visual impairment …

Newly added information:

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 less than or equal to21 years of age and were required to have an absolute neutrophil count greater than or equal to 1000/mm3 (750/mm3 if bone marrow was involved), platelet count greater than or equal to 75,000/mm3 (25,000/mm3 if bone marrow was involved), creatinine clearance greater than or equal to 70ml/min/1.73m2, and QTc less than or equal to480 msec. The study excluded patients with ALT >2.5 times upper limit of normal (ULN), bilirubin less than or equal to1.5 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 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, respectively. XALKORI was discontinued for an adverse reaction in 8% of patients.

The most common adverse reactions (greater than or equal to 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 (greater than or equal to 15%) included neutropenia, lymphopenia, and thrombocytopenia. Grade 4 laboratory abnormalities (greater than or equal to 15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%).

Selected adverse reactions are summarized in Table 11.

Table 11. Adverse Reactions in greater than or equal to 20% of Patients with Systemic ALCL in Study ADVL0912 Newly added table; please refer to label for complete information.

Newly added information:

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 Disorder: Acute renal injury (8%)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:
The safety and effectiveness of XALKORI have been established in pediatric patients 12 months of age and older with relapsed or refractory, systemic ALK-positive ALCL [see Adverse Reactions (6.1), Clinical Studies (14.2)]. The safety and effectiveness have not been established in pediatric patients younger than 12 months of age with ALCL 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 …

8.7 Renal Impairment

Additions and/or revisions underlined:

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 …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Label had a Patient Information Sheet component, which had similar information to this Medication Guide.

What is the most important information I should know about XALKORI? XALKORI may cause serious side effects, including:

Additions and/or revisions underlined:

·         Severe vision problems.

After the bulleted symptom list, the following new information is added:

In addition, for people taking XALKORI to treat anaplastic large cell lymphoma (ALCL): Your healthcare provider may refer you to an eye specialist before starting XALKORI, and within 1 month of starting XALKORI to check for vision problems. You should have an eye examination every 3 months during treatment with XALKORI and more often if there are any new vision problems.

·         Severe stomach, intestine, and mouth (gastrointestinal) problems in people with ALCL. XALKORI may cause severe diarrhea, nausea, vomiting, or mouth sores. Tell your healthcare provider right away if problems with swallowing, vomiting, or diarrhea develop during treatment with XALKORI.

o   Your healthcare provider may give medicines as needed to prevent or treat diarrhea, nausea, and vomiting.

o   Your healthcare provider may recommend drinking more fluids or may prescribe electrolyte supplements or other kinds of nutritional support if severe symptoms develop.

What is XALKORI?

XALKORI is a prescription medicine that is used to treat:

Newly added information:

·         children 1 year of age and older and young adults when your ALCL with a defect in a gene called ALK has returned, or you have tried a treatment and it did not work or is no longer working.

Additions and/or revisions underlined:

It is not known if XALKORI is safe and effective in children under 12 months of age or in older adults with ALCL.

Before taking XALKORI, tell your healthcare provider about all of your medical conditions, including if you:

Additions and/or revisions underlined:

·         have lung problems

·         are pregnant, or plan to become pregnant. XALKORI can harm the unborn baby.

Females who are able to become pregnant:

o   Your healthcare provider will check to see if you are pregnant before starting treatment with XALKORI.

o   Effective birth control (contraception) should be used during treatment with XALKORI and for at least 45 days after the final dose of XALKORI.

o   Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with XALKORI.

Males who have female partners who can become pregnant:

o   You should use condoms during treatment with XALKORI and for at least 90 days after the final dose of XALKORI.

How should I take XALKORI?

o   XALKORI should be given to children under adult supervision.

Newly added information:

The most common side effects of XALKORI in people with ALCL include:

·         diarrhea, vomiting, or nausea

·         vision problems

·         headache

·         muscle and joint pain

·         mouth sores

·         tiredness

·         decreased appetite

·         fever

·         stomach-area (abdominal) pain

·         cough

·         itchy skin

·         low blood counts

·         abnormal liver tests

·         low levels of electrolytes

·         abnormal kidney tests

·         low and high blood sugar levels

General information about the safe and effective use of XALKORI.

Additions and/or revisions underlined:

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XALKORI for a condition for which it was not prescribed …

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Newly added information:

Gastrointestinal Toxicity in Patients with ALCL

Inform patients with ALCL of the risk of severe nausea, vomiting, diarrhea, and stomatitis. Advise patients to immediately inform their healthcare provider of problems with swallowing, vomiting, or diarrhea [see Warnings and Precautions (5.6)].

06/25/2019 (SUPPL-28)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(new subsection added)

The following additional adverse reaction has been identified during postapproval 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

7.3 Drugs That Prolong the QT Interval

(new subsection added)

XALKORI can prolong the QT/QTc interval. Avoid concomitant use of XALKORI with drugs that prolong the QT interval.

7.4 Drugs That Cause Bradycardia

(new subsection added)

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).

8 Use in Specific Populations

8.1 Pregnancy

(addition underlined)

Based on findings from animal studies and its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman.

…

8.2 Lactation

(addition underlined)

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 final dose.

8.3 Females and Males of Reproductive Potential

(additions underlined)

Pregnancy Testing

 

Verify the pregnancy status of females of reproductive potential prior to initiating XALKORI.

 

Contraception

 

XALKORI can cause fetal harm when administered to a pregnant woman

…

8.6 Hepatic Impairment

(additions underlined)

 

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. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment . 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).

8.7 Renal Impairment

(additions underlined)

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) not requiring dialysis, therefore reduce dosage of XALKORI in these patients. No dose adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min).

12/06/2018 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hepatotoxicity

(subsection revised, additions and revisions underlined)

Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.1%) of the 1719 patients treated with XALKORI across clinical trials. Concurrent elevations in alanine aminotransferase (ALT) or AST greater than or equal to 3 times the ULN and total bilirubin greater than or equal to 2 times the ULN, with normal alkaline phosphatase, occurred in 10 patients (<1%) treated with XALKORI. Elevations in ALT or AST greater than 5 times the ULN occurred in 187 (11.2%) and 95 (5.7%) patients, respectively. Seventeen patients (1.0%) required permanent discontinuation due to elevated transaminases. Transaminase elevations generally occurred within the first 2 months of treatment.

…

Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2.

5.2 Interstitial Lung Disease (Pneumonitis)

(additions underlined)

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1719), 50 XALKORI-treated patients (2.9%) had ILD of any grade, 18 patients (1.0%) had Grade 3 or 4 ILD, and 8 patients (0.5%) had fatal ILD. Interstitial lung disease generally occurred within 3 months after the initiation of XALKORI.

…

5.3 QT Interval Prolongation

(subsection revised, additions and revisions underlined)

QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 34 of 1616 patients (2.1%) had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 500 ms and

79 of 1582 patients (5.0%) had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECGs.

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. Permanently discontinue XALKORI in patients who develop 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. Withhold XALKORI in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume XALKORI at a reduced dose as described in Table 2.

5.4 Bradycardia

(subsection revised, additions and revisions underlined)

 

Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia occurred in 219 (12.7%) 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.

Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

6 Adverse Reactions

6.1 Clinical Trials Experience

(minor revisions, please refer to label for more information)

7 Drug Interactions

7.1 Drugs That May Increase Crizotinib Plasma Concentrations

 (additions underlined)

 

Coadministration of crizotinib with strong cytochrome P450 (CYP) 3A inhibitors increases crizotinib plasma concentrations. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, troleandomycin, voriconazole, grapefruit, and grapefruit juice. If the use of strong CYP3A inhibitors cannot be avoided, reduce the dose of XALKORI to 250 mg orally once daily. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor. Exercise caution with concomitant use of moderate CYP3A inhibitors.

7.2 Drugs That May Decrease Crizotinib Plasma Concentrations

(additions underlined)

Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations. Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort.

7.3 Drugs Whose Plasma Concentrations May Be Altered By Crizotinib

(additions underlined)

Crizotinib inhibits CYP3A both in vitro and in vivo.  Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking XALKORI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

…

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

…

8.7 Renal Impairment

(additions underlined)

 

Increased exposure to crizotinib occurred in patients with pre-existing severe renal impairment

(CLcr <30 mL/min) not requiring dialysis. Administer XALKORI at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis. No dose adjustment is recommended in patients with mild to moderate renal impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Females and Males of Reproductive Potential

Advise females and males of reproductive potential of the potential for reduced fertility from XALKORI.

…

11/30/2018 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

Minor editorial changes throughout subsections; please refer to label for complete information.

6 Adverse Reactions

6.1 Clinical Trials Experience

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

Data in this subsection has been rounded up or down.

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

7 Drug Interactions

7.1 Effect of Other Drugs on XALKORI

Strong or Moderate CYP3A Inhibitors

Strong CYP3A Inducers

7.2 Effect of XALKORI on Other Drugs

CYP3A Substrates

Numerous changes made to the above two subsections; please refer to label for complete information.

The following two subsections are newly added:

7.3 Drug That Prolong the QT Interval

XALKORI can prolong the QT/QTc interval. Avoid concomitant use of XALKORI with drugs that prolong the QT interval.

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).

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

Based on findings from animal studies and its mechanism of action

8.2 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 final dose.

8.3 Females and Males of Reproductive Potential

Addition of the following:

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating XALKORI.

8.4 Pediatric Use

Juvenile and Toxicity added below:

Juvenile Animal Toxicity Data

8.6 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. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment. 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).

8.7 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) not requiring dialysis, therefore reduce dosage of XALKORI in these patients. No dose adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min).

02/07/2018 (SUPPL-23)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.7 Renal Impairment

Additions and/or revisions underlined:

Increased exposure to crizotinib occurred in patients with pre-existing severe renal impairment (CLcr less than 30 mL/min) not requiring dialysis. Administer XALKORI at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis.  No dose adjustment is recommended in patients with mild to moderate renal impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

8.6 Hepatic Impairment

Additions and/or revisions underlined:

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.  Reduce XALKORI dose in patients with moderate or severe hepatic impairment.  No dose adjustment is recommended in patients with pre-existing mild hepatic impairment.

01/24/2017 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Table 3. Adverse Reactions Reported at a Higher Incidence (Greater than or Equal to 5% Higher for All Grades or Greater than or Equal to 2% Higher for Grades 3-4) with XALKORI than Chemotherapy in Study 1 (Table has been revised with the addition of esophagitis to the adverse reactions listed; please refer to label)

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included… and decreased blood testosterone (1%; hypogonadism).

Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included…esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism).

04/29/2016 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

Renal impairment

• 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.