XALKORI

Crizotinib is a kinase inhibitor.

The molecular formula for crizotinib is

C 21 H 22 Cl 2 FN 5 O and the molecular weight is 450.34 daltons.

Crizotinib is described chemically as ( R )-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1 H -pyrazol-4-yl]pyridin-2-amine.

The chemical structure of crizotinib is shown below: Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation).

The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL.

The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.

XALKORI (crizotinib) capsules for oral administration are supplied as printed hard-shell capsules containing 250 mg or 200 mg of crizotinib together with colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, and hard gelatin capsule shells as inactive ingredients.

The pink opaque capsule shell components contain gelatin, titanium dioxide, and red iron oxide.

The white opaque capsule shell components contain gelatin and titanium dioxide.

The printing ink contains shellac, propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide.

XALKORI (crizotinib) oral pellets for oral administration are supplied as 20 mg, 50 mg, 150 mg of crizotinib contained in hard gelatin capsules.

The inactive ingredients in the uncoated pellets are poloxamer and stearyl alcohol.

The film-coating consists of hypromellose, glyceryl monostearate, medium chain triglycerides, polyethylene glycol/macrogol, sucrose, and talc.

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.

• 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. o Limitations 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. 1.1 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. 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.

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.

Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON).

Translocations can affect the

ALK gene resulting in the expression of oncogenic fusion proteins.

The formation of

ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins.

Crizotinib demonstrated concentration-dependent inhibition of

ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4).

• or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

In vitro, crizotinib induced apoptosis and inhibited proliferation and ALK-mediated signaling in ALCL-derived cell lines (containing NPM-ALK) at clinically achievable exposures.

In vivo data obtained in an

ALCL-derived mouse model showed complete regression of the tumor at a dose of 100 mg/kg once daily. 12.2 Pharmacodynamics Cardiac Electrophysiology In an ECG substudy conducted in 52 patients with ALK-positive NSCLC, the maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was 12.3 ms (2-sided 90% upper CI: 19.5 ms) following administration of XALKORI 250 mg orally twice daily.

An exposure-QT analysis suggested a crizotinib plasma concentration-dependent increase in QTcF. 12.3 Pharmacokinetics Following XALKORI 250 mg capsules twice daily, steady-state was reached within 15 days with a median accumulation ratio of 4.8.

Steady-state minimum concentration (C min.ss ) and AUC increased in a greater than dose-proportional manner over the dose range of 200 mg to 300 mg twice daily (0.8 to 1.2 times the approved recommended dosage).

A single crizotinib capsule dose was absorbed with median time to achieve peak concentration (T max ) of to 6 hours, and the mean absolute bioavailability of 43% (range: 32% to 66%).

The oral pellets had a comparable crizotinib bioavailability compared with the capsules.

A high-fat meal, reduced AUC 0-INF and maximum plasma concentration (C max ) of crizotinib each by 14% for the capsule formulation; reduced AUC 0-INF and C max of crizotinib by 15% and 23%, respectively, for the pellet formulation as compared to those under fasted conditions.

The geometric mean volume of distribution (V ss ) of crizotinib was 1772 L following a single intravenous dose.

Protein binding of crizotinib is 91% and is independent of drug concentration in vitro.

Crizotinib is a substrate for

P-glycoprotein (P-gp) in vitro.

The blood-to-plasma concentration ratio is approximately 1.

The mean apparent plasma terminal half-life of crizotinib was 42 hours following single doses of crizotinib in patients.

The mean apparent clearance (CL/F) of crizotinib was lower at steady-state (60 L/h) after 250 mg twice daily than after a single 250 mg oral dose (100 L/h).

Metabolism Crizotinib is predominantly metabolized by

Following administration of a single oral 250 mg dose of radiolabeled crizotinib dose to healthy subjects, 63% (53% as unchanged) of the administered dose was recovered in feces and 22% (2.3% as unchanged) in urine.

No clinically significant difference in crizotinib pharmacokinetics were observed based on age, sex, or ethnicity (Asian, non-Asian).

For patients <18 years of age, body weight has a significant effect on the pharmacokinetics of crizotinib, with lower crizotinib exposures observed in patients with higher body weight.

In pediatric patients, crizotinib steady-state exposure increased proportionally with dose over the dose range of 165 mg/m to 280 mg/m 2 orally twice daily.

At a dosing regimen of 280 mg/m 2 (approximately 2 times the recommended adult dose), geometric mean (CV%) steady-state maximum plasma concentrations (C max ) of crizotinib was 621 (73%) ng/mL and AUC 0–tau was 6530 (34%) ng∙hr/mL.

Patients with Hepatic Impairment Steady-state mean crizotinib AUC and C max decreased by 9% in patients with mild hepatic impairment (AST >ULN and total bilirubin ≤1 times ULN or any AST and total bilirubin >1 times ULN but ≤1.5 times ULN) compared to patients with normal hepatic function following XALKORI 250 mg orally twice daily.

Steady-state mean crizotinib

AUC increased by 14% and C max increased by 9% in patients with moderate hepatic impairment (any AST and total bilirubin >1.5 times ULN and ≤3 times ULN) following XALKORI 200 mg orally twice daily compared with patients with normal hepatic function following XALKORI 250 mg orally twice daily.

Mean crizotinib

AUC decreased by 35% and C max decreased by 27% in patients with severe hepatic impairment (any AST and total bilirubin >3 times ULN) following XALKORI 250 mg orally once daily compared with patients with normal hepatic function following XALKORI 250 mg orally twice daily.

Mild or moderate renal impairment (CL cr of 60–89 ml/min or 30–59 ml/min, respectively, calculated using the modified Cockcroft-Gault equation) has no clinically significant effect on the exposure of crizotinib.

Following a single 250 mg dose, the mean AUC 0–INF of crizotinib increased by 79% and the mean C max increased by 34% in patients with severe renal impairment (CL cr <30 mL/min) who did not require dialysis compared to those with normal renal function (CL cr ≥90 mL/min).

Similar changes in

AUC 0–INF and C max were observed for the active metabolite of crizotinib.

Drug Interaction Studies Clinical Studies Gastric Acid Reducing Agents: No clinically significant differences in crizotinib pharmacokinetics were observed when used concomitantly with esomeprazole, a proton pump inhibitor.

CYP3A Inhibitors: Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole, a strong CYP3A inhibitor, increased crizotinib AUC 0–INF by 216% and C max by 44% compared to crizotinib alone.

Coadministration of

XALKORI 250 mg orally once daily with itraconazole, a strong CYP3A inhibitor, increased crizotinib steady-state AUC by 57% and C max by 33% compared to crizotinib alone.

CYP3A Inducers: Coadministration of XALKORI 250 mg orally twice daily with rifampin, a strong CYP3A inducer, decreased crizotinib steady-state AUC 0–Tau by 84% and C max by 79%, compared to crizotinib alone.

CYP3A Substrates: Coadministration of XALKORI 250 mg orally twice daily for 28 days increased AUC 0–INF of oral midazolam (CYP3A substrate) 3.7-fold compared to midazolam alone.

Crizotinib inhibits CYP2B6 in vitro.

Crizotinib does not inhibit

Crizotinib does not induce

UDP-glucuronosyltransferase (UGT): Crizotinib does not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7.

Crizotinib inhibits P-gp, organic cation transporter (OCT) 1, and OCT2.

Crizotinib does not inhibit organic anion transporting polypeptides (OATP) B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, or bile salt export pump transporter (BSEP).

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

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.

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

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.

To report SUSPECTED ADVERSE

REACTIONS, contact Pfizer Inc.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 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).

• 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 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.

• Study 1 (PROFILE 1014) The data in Table 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/m with cisplatin 75 mg/m 2 (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 and 10 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 9.

Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3–4) with XALKORI than Chemotherapy in Study 1 Adverse 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 Bradycardia Bradycardia (Bradycardia, Sinus bradycardia). 14 1 1 0 Electrocardiogram QT prolonged 6 2 2 0 Eye Vision disorder Vision 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 pain Abdominal 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 Esophagitis Esophagitis (Esophagitis, Esophageal ulcer). 6 2 1 0 General Edema Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema). 49 1 12 1 Pyrexia 19 0 11 1.

Infections Upper respiratory infection Upper 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 Dizziness Dizziness (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%).

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 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2).

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/m 2 (n=99) or docetaxel 75 mg/m 2 (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 and 12 summarize common adverse reactions and laboratory abnormalities, respectively, in XALKORI-treated patients.

Table 11.

Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3–4) with XALKORI than Chemotherapy in Study 2 Adverse 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 Dizziness Dizziness (Balance disorder, Dizziness, Postural dizziness). 22 1 8 0 Syncope 3 3 0 0 Eye Vision disorder Vision 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 Bradycardia Bradycardia (Bradycardia, Sinus bradycardia). 5 0 0 0.

Investigations Decreased weight 10 1 4 0 Gastrointestinal Diarrhea 60 0 19 1 Na.

The recommended dosage is 250 mg orally twice daily.

• Systemic ALCL: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area.

• Unresectable IMT: o Adult: The recommended dosage is 250 mg orally twice daily. o Pediatric: The recommended dosage is 280 mg/m 2 orally twice daily based on body surface area.

• See full prescribing information for dosage adjustments by indication for patients with moderate or severe hepatic impairment or severe renal impairment. 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.

Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at. 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.

• 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.

• 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. 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/m 2 orally twice daily See Table 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/m 2 orally twice daily See Table 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

• 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.

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/m 2 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 m 2 120 mg twice daily 1 x 20 mg + 2 x 50 mg --

• 0.47 to 0.51 m 2 140 mg twice daily 2 x 20 mg + 2 x 50 mg --

• 0.52 to 0.61 m 2 150 mg twice daily 1 x 150 mg --

• 0.62 to 0.80 m 2 200 mg twice daily 1 x 50 mg + 1 x 150 mg --

• 0.81 to 0.97 m 2 250 mg twice daily 2 x 50 mg + 1 x 150 mg --

• 0.98 to 1.16 m 2 300 mg twice daily 2 x 150 mg --

• 1.17 to 1.33 m 2 350 mg twice daily 1 x 50 mg + 2 x 150 mg --

• 1.34 to 1.51 m 2 400 mg twice daily 2 x 50 mg + 2 x 150 mg 2 x 200 mg 1.52 to 1.69 m 2 450 mg twice daily 3 x 150 mg 1 x 200 mg + 1 x 250 mg 1.7 m 2 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.

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/m 2 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.

• 1.34 to 1.51 m 2 400 mg twice daily 2 x 50 mg + 2 x 150 mg 2 x 200 mg 1.52 to 1.69 m 2 450 mg twice daily 3 x 150 mg 1 x 200 mg + 1 x 250 mg 1.7 m 2 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.

• Swallow XALKORI capsules whole, with or without food twice daily.

• Do not chew, crush or split XALKORI capsules.

• 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).

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. 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 m 2 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 m 2 100 mg twice daily Pellets: 2 x 50 mg 80 mg twice daily Pellets: 4 x 20 mg 0.52 to 0.61 m 2 120 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 m 2 150 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 m 2 200 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 m 2 220 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 m 2 250 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 m 2 250 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 m 2 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.

XALKORI Dosage Modification – Hematologic Toxicities Except 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.

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 10 9 /L First occurrence: Withhold until recovery to ANC greater.

• 200 mg capsules Hard gelatin capsule with pink opaque cap and white opaque body, printed with black ink "Pfizer" on the cap, "CRZ 200" on the body; available in: Bottles of 60 capsules: NDC 0069-8141-20.

• 250 mg capsules Hard gelatin capsule with pink opaque cap and body, printed with black ink "Pfizer" on the cap, "CRZ 250" on the body; available in: Bottles of 60 capsules: NDC 0069-8140-20 Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) .

• 20 mg oral pellets Hard gelatin capsule, size 4, light blue opaque cap and white opaque body, printed with black ink “Pfizer” on the cap, “CRZ 20” on the body; available in: Bottles of 60 capsules: NDC 0069-0251-60.

• 50 mg oral pellets Hard gelatin capsule, size 3, gray opaque cap and light gray opaque body, printed with black ink “Pfizer” on the cap, “CRZ 50” on the body; available in: Bottles of 60 capsules: NDC 0069-0507-60.

• 150 mg oral pellets Hard gelatin capsule, size 0, light blue opaque cap and body, printed with black ink “Pfizer” on the cap, “CRZ 150” on the body; available in: Bottles of 60 capsules: NDC 0069-1500-60 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) .

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

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.

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.

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.

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.

The safety and effectiveness have not been established in pediatric patients younger than 1 year of age with ALCL or with IMT, or in any pediatric patients with NSCLC.

In a study that evaluated

XALKORI in combination with chemotherapy in pediatric patients with newly diagnosed ALCL (Study ANHL12P1; NCT01979536), 13 of 66 (20%) patients had a Grade 2 or higher thromboembolic event, including pulmonary embolism in 6%.

XALKORI in combination with chemotherapy have not been established in patients with newly diagnosed ALCL.

Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 5.4 times the recommended human dose based on AUC).

Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Of the total number of patients with ALK-positive metastatic NSCLC in clinical studies of XALKORI (n=1669), 16% were 65 years or older and 3.8% were 75 years or older.

No overall differences in safety or effectiveness were observed between these patients and younger patients.

Clinical studies of XALKORI in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.