crizotinib (Xalkori)

Dosing and uses of Xalkori (crizotinib)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

capsules

• 200mg
• 250mg

 

Non-Small Cell Lung Cancer

Indicated for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase-positive as detected by an FDA-approved test

Also indicated for metastatic NSCLC tumors that are ROS1-positive

Select patients for treatment of metastatic NSCLC based on presence of ALK or ROS1 positivity in tumor specimens

250 mg PO q12hr

Continue treatment as long as patient is deriving clinical benefit from therapy

 

Dose Modifications

Dosing interruption and/or dose reduction to 200 mg PO q12hr may be required based on safety and tolerability; decrease to 250 mg PO qDay if further reduction is needed

The intensity of clinical adverse events graded by the NCI Common Terminology Criteria for Adverse Events

Hematologic toxicities

• Dose modifications are for all hematologic toxicities except lymphopenia (unless associated with clinical events, eg, opportunistic infections)
• Grade 3 AE: Withhold until recovery to Grade ≤2, then resume at the same dose schedule
• Grade 4 AE: Withhold until recovery to Grade ≤2, then resume at 200 mg PO q12hr (in case of recurrence, withhold until recovery to Grade ≤2, then resume at 250 mg PO qDay; permanently discontinue in case of Grade 4 recurrence)

Nonhematologic toxicities

• Grade 3 or 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation with Grade ≤1 total bilirubin: Withhold until recovery to Grade ≤1 or baseline, then resume at 200 mg PO q12hr (in case of recurrence, withhold until recovery to Grade ≤1, then resume at 250 mg PO qDay; permanently discontinue in case of further Grade 3 or 4 recurrence)
• Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3, or 4 total bilirubin elevation (in absence of cholestasis or hemolysis): Permanently discontinue
• Any Grade pneumonitis: Permanently discontinue
• Grade 3 QTc prolongation: Withhold until recovery to Grade ≤1, then resume at 200 mg PO q12hr
• Grade 4 QTc prolongation: Permanently discontinue

Bradycardia

• Symptomatic bradycardia: Withhold until recovery to asymptomatic bradycardia or HR ≥60 bpm; if patient taking other drugs that cause bradycardia, adjust dose (or if possible discontinue); if patient is not taking other drugs that cause bradycardia
• Life-threatening bradycardia: Permanently discontinue if no contributing concomitant medication identified; if other drug identified and discontinued, or its dose is adjusted, resume crizotinib at 250 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm with frequent monitoring

 

Renal & Hepatic Impairment

Hepatic impairment: Caution advised

Renal impairment

• Mild-to-moderate (CrCl 30-90 mL/min): No starting dose adjustment is needed; steady-state trough concentrations in these 2 groups were similar to those with normal renal function (ie, CrCl >90 mL/min)
• Severe (CrCl <30 mL/min) or end-stage renal disease: Caution advised

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Geriatric dosage forms and strengths

No overall differences in safety or efficacy were observed in comparison with younger patients

 

Xalkori (crizotinib) adverse (side) effects

>10%

ALT elevation (76%)

AST elevation (61%)

Vision disorder (60%)

Diarrhea (60%)

Nausea (55%)

Lymphopenia (51%)

Neutropenia (49%)

Vomiting (47%)

Constipation (42%)

Edema (31%)

Hypophosphatemia (28%)

Decreased appetite (27%)

Fatigue (27%)

Dysgeusia (26%)

Upper respiratory infection (26%)

Dizziness (22%)

Neuropathy (19%)

Dysesthesia (19%)

Gait disturbance (19%)

Hypoesthesia (19%)

Muscular weakness (19%)

Neuralgia (19%)

Peripheral neuropathy (19%)

Paresthesia (19%)

Peripheral sensory neuropathy (19%)

Polyneuropathy (19%)

Burning sensation in skin (19%)

Hypokalemia (18%)

 

1-10%

Weight decreased (10%)

Rash (9%)

Dyspepsia (8%)

Pulmonary embolism (6%)

QT prolongation (5%)

Bradycardia (5%)

Pneumonia (4.1%)

Pneumonitits (4%)

Renal cyst (4%)

ARDS (4%)

Pulmonary embolism (3.5%)

Syncope (3%)

Dyspnea (2.3%)

Hepatic failure (1%)

 

<1%

Vision loss, grade 4 (0.2%)

 

Warnings

Contraindications

Hypersensitivity

 

Cautions

Severe, including fatal, treatment-related pneumonitis reported; monitor for pulmonary symptoms indicative of pneumonitis and permanently discontinue if diagnosed

Hepatoxicity reported; elevations in ALT and total bilirubin reported; monitor q2wk for 2 months, then monthly and as clinically indicated with more frequent testing with Grade 2-4 elevations; temporarily suspend, reduce dose, or permanently discontinue dose as indicated (see Dose Modifications)

Symptomatic bradycardia reported, including syncope; avoid coadministration with other drugs known to cause bradycardia; monitor heart rate and blood pressure regularly; temporarily suspend, reduce dose, or permanently discontinue (see Dosage modifications)

Caution when driving or operating machinery because of vision disorder, dizziness, or fatigue associated with treatment

Can cause fetal harm when administered to pregnant women (see Pregnancy)

Interstitial Lung Disease (ILD)/Pneumonitis reported; permanently discontinue in patients with ILD/pneumonitis

Visual field defect with vision loss reported; optic atrophy and optic nerve disorder have been reported as potential causes of vision loss; discontinue with new onset of severe visual loss

QT Effects

• QTc prolongation reported
• Avoid use with congenital long QT syndrome
• In patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those taking medications known to prolong QT interval, consider periodic ECG and electrolye monitoring
• Permanently discontinue with Grade 4 QTc prolongation
• Withhold dose with Grade 3 QTc prolongation (see Dose Modifications)

 

Pregnancy and lactation

 

Pregnancy

Based on its mechanism of action, can cause fetal harm when administered to a pregnant woman

In animal reproduction studies, administration in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for at least 45 days following the final dose
• Advise males taking crizotinib with female partners of reproductive potential to use condoms during treatment and for at least 90 days after the final dose

 

Lactation

There is no information regarding the presence of crizotinib in human milk, the effects on the breastfed infant, or the effects on milk production

Because of the potential for adverse reactions in breastfed infants, do not breastfeed during treatment and for 45 days after the final dose

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Xalkori (crizotinib)

Mechanism of action

Inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON)

The gene’s expression and signaling that contribute to increased cell proliferation and survival of the tumors become activated following the expression of ALK oncogenic fusion proteins

Inhibits the signaling that promotes the expression of these oncogenic fusion proteins, thereby inhibiting tumor cell proliferation

 

Absorption

Bioavailability: 43% (mean absolute bioavailability)

Peak Plasma Time: 4-6 hr

 

Distribution

Protein Bound: 91% to human plasma proteins, independent of drug concentration

Vd: 1772 L, following 50 mg IV dose, indicating extensive distribution into tissues from plasma

P-glycoprotein (P-gp) substrate and inhibitor

 

Metabolism

Predominantly metabolized by CYP3A4/5

Time-dependent inhibitor of CYP3A

Primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites

 

Elimination

Half-life: 42 hr

Total body clearance: 60 L/hr (250 mg PO q12hr); 100 L/hr (250 mg PO qDay)

Excretion: Feces 63%; urine 22%

 

Pharmacogenomics

Patient selection for treatment is based on presence of ALK fusion gene

Verify presence of ALK fusion gene by using the diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit

 

Administration

Oral Administration

Take with or without food; a high-fat meal reduces AUCinf and Cmax by ~14%

Capsules should be swallowed whole

Missed dose

• Instruct patient to take a missed dose as soon as they remember, except if the next dose is scheduled within the next 6 hr (ie, do not take a missed dose within 6 hr of the next dose)
• Patients should not take 2 doses at the same time to make up for a missed dose