XALKORI

Crizotinib is a tyrosine kinase receptor inhibitor used for the treatment of anaplastic lymphoma kinase (ALK) or ROS1-positive non-small cell lung cancer (NSCLC) tumors, as well as ALK-positive anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT).

By targeting the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein, crizotinib offers robust effectiveness in treating NSCLC in patients with this type of rearrangement.

Crizotinib was the first-in-class drug used to treat ALK-positive tumors.

• and third-generation ALK-tyrosine kinase-inhibitors have overcome many of the pharmacodynamic and genetic resistance mechanisms crizotinib is prone to.

Crizotinib was approved by the

FDA in 2011, and its use is accompanied by FDA-approved tests used to detect ALK and ROS1 rearrangements.

Crizotinib is a kinase inhibitor indicated for the treatment of 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.

Crizotinib is also indicated for the treatment of relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients 1 year of age and older and young adults.

The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.

Additionally, crizotinib 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.

In a phase

I study, 37 patients with a variety of solid-tumor cancers refractory to therapy received 50-300 mg of crizotinib daily or twice daily.

In this group, two patients with non-small cell lung cancer (NSCLC) exhibiting echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) mutations responded to therapy; therefore, following studies focused on patients with advanced ALK-positive disease.

In this group of patients, the 6-month progression-free survival among crizotinib users was approximately 72%.

When compared to

ALK mutation-positive patients that did not receive crizotinib, ALK mutation-positive patients treated with crizotinib had a higher two-year overall survival rate (54% vs 36%).

The use of crizotinib may lead to hepatotoxicity, interstitial lung disease (ILD), pneumonitis, QT interval prolongation, bradycardia, severe visual loss, ​​embryo-fetal toxicity and gastrointestinal toxicity in pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumor (IMT).

tyrosine kinase receptor Inhibitor Hepatocyte growth factor receptor Inhibitor Proto-oncogene tyrosine-protein kinase ROS Inhibitor + 1 more target.

In patients with pancreatic, colorectal, sarcoma, anaplastic large-cell lymphoma and non-small cell lung cancer (NSCLC) treated with crizotinib doses ranging from 100 mg once a day to 300 mg twice a day, the mean AUC and C max increased in a dose-proportional manner.

A single crizotinib dose of crizotinib is absorbed with a median t max 4-6 hours.

In patients receiving multiple doses of crizotinib 250 mg twice daily (n=167), the mean AUC was is 2321.00 ng⋅hr/mL, the mean C max was 99.60 ng/mL, and the median t max was 5.0 hours.

The mean absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%.

High-fat meals reduce the

AUC 0-INF and C max of crizotinib by approximately 14%.

Age, sex at birth, and ethnicity (Asian vs non-Asian patients) did not have a clinically significant effect on crizotinib pharmacokinetics.

In patients less than 18 years old, higher body weight was associated with a lower crizotinib exposure.

Following a single intravenous dose, the mean volume of distribution (Vss) of crizotinib was 1772 L.

Crizotinib is mainly metabolized in the liver by CYP3A4 and CYP3A5, and undergoes an O-dealkylation, with subsequent phase 2 conjugation.

Non-metabolic elimination, such as biliary excretion, can not be excluded.

PF-06260182 (with two constituent diastereomers, PF-06270079 and PF-06270080) is the only active metabolite of crizotinib that has been identified.

In vitro studies suggest that, compared to crizotinib, PF-06270079 and PF-06270080 are approximately 3.

• to 8-fold less potent against anaplastic lymphoma kinase (ALK) and 2.5.

• to 4-fold less potent against Hepatocyte Growth Factor Receptor (HGFR, c-Met).

Hover over products below to view reaction partners Crizotinib PF-06260182.

After administering a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose were recovered in feces and urine.

Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.

Following single doses of crizotinib, the plasma terminal half-life was 42 hours.

At steady-state (250 mg twice daily), crizotinib has a mean apparent clearance (CL/F) of 60 L/hr. This value is lower than the one detected after a single 250 mg oral dose (100 L/hr), 4, possibly due to CYP3A auto-inhibition.

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The maximum tolerated dose of crizotinib is the same as the recommended dosing regimen (250 mg twice daily).

This was defined based on a phase 1 dose-escalation study in patients with advanced solid tumors.

The treatment of crizotinib overdoses should consist of symptomatic treatment and other supportive measures.

There is no antidote for crizotinib.

In vitro and in vivo studies have shown that crizotinib is genotoxic, and the Ames test showed that crizotinib was not mutagenic.

Carcinogenicity studies with crizotinib have not been performed.

In female rats, 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) of crizotinib for 3 days induced single-cell necrosis of ovarian follicles.

In male rats, 50 mg/kg/day of crizotinib (greater than 1.7 times the recommended human dose) for 28 days induced testicular pachytene spermatocyte degeneration.

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.