kriz-OH-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• Metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK) or ROS1.
• Relapsed or refractory, systemic anaplastic large cell lymphoma that is positive for ALK.
• Unresectable, recurrent, or refractory inflammatory myofibroblastic tumor that is positive for ALK.

• Inhibits receptor tyrosine kinases, including anaplastic lymphoma kinase, hepatocyte growth factor receptor, ROS1, and recepteur d'origine nantais.

• Decreased spread of lung cancer and improved survival.
• Decreased spread of systemic anaplastic large cell lymphoma or inflammatory myofibroblastic tumor.

Absorption: 43% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Mostly metabolized by the liver (CYP3A4/5 isoenzymes); also acts as an inhibitor of CYP3A. 53% excreted in feces unchanged, 2.3% eliminated unchanged in urine.

Half-life: 42 hr.

(plasma concentrations)

Contraindicated in:

• Concurrent use of strong CYP3A inhibitors or inducers
• Congenital long QT syndrome
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Heart failure, bradyarrhythmias, electrolyte abnormalities, concurrent medications that prolong QT interval (↑ risk of arrhythmias)
• Asian patients (↑ blood levels)
• Moderate or severe hepatic impairment (↓ dose)
• Severe renal impairment
• Women of reproductive potential and men with female sexual partners of reproductive potential
• Pedi: Safety and effectiveness not established in children <18 yr (NSCLC) or <1 yr (anaplastic large cell lymphoma or inflammatory myofibroblastic tumor).

CV: bradycardia, edema, QT interval prolongation, chest pain.

Derm: rash.

EENT: visual disturbances.

Endo: ↓testosterone.

GI: ↑liver enzymes, constipation, diarrhea, nausea, stomatitis, vomiting, ↓ appetite, abdominal pain, esophagitis, HEPATOTOXICITY.

GU: ↓fertility, renal impairment.

Neuro: dysgeusia, fatigue, headache, insomnia, neuropathy.

Resp: INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS.
Misc: fever.

Drug-Drug:

• Strong CYP3A inhibitors, including atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, and voriconazole, may ↑ levels; concurrent use should be avoided; if concurrent use unavoidable, ↓ crizotinib dose.
• Strong CYP3A inducers, including carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin, may ↓ levels and effectiveness; concurrent use should be avoided.
• May ↑ levels of cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus; avoid concurrent use.
• Beta blockers, verapamil, diltiazem, digoxin, and clonidine may ↑ risk of bradycardia; avoid concurrent use, if possible.

Drug-Natural Products:

• Concurrent use of St. John's wort may ↓ levels and effectiveness and should be avoided.

Drug-Food:

• Grapefruit or grapefruit juice may ↑ levels and should be avoided.

Non-Small Cell Lung Cancer

• PO (Adults): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Systemic Anaplastic Large Cell Lymphoma

• PO (Children 1 yr and body surface area [BSA] 1.70 m²): 500 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 1.52–1.69 m²): 450 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 1.34–1.51 m²): 400 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 1.17–1.33 m²): 350 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.98–1.16 m²): 300 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 170 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.81–0.97 m²): 250 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 150 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.62–0.80 m²): 200 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 120 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.52–0.61 m²): 150 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 90 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.47–0.51 m²): 140 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 80 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.38–0.46 m²): 120 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 70 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.

Inflammatory Myofibroblastic Tumor

• PO (Adults): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg once daily. Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 1.70 m²): 500 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 1.52–1.69 m²): 450 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 1.34–1.51 m²): 400 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily (oral pellets or capsules). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 1.17–1.33 m²): 350 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.98–1.16 m²): 300 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 170 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.81–0.97 m²): 250 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 150 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.62–0.80 m²): 200 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 120 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.52–0.61 m²): 150 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 90 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.47–0.51 m²): 140 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 80 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.
• PO (Children 1 yr and BSA 0.38–0.46 m²): 120 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 70 mg twice daily (oral pellets). Continue until disease progression or unacceptable toxicity.

• Capsules: 200 mg; 250 mg;
• Oral pellets: 20 mg; 50 mg; 150 mg;

• Assess respiratory function (lung sounds, dyspnea, oxygen saturation) periodically during therapy.
• Monitor for signs and symptoms of ILD/pneumonitis (difficulty breathing, shortness of breath, cough with or without mucus, fever) periodically during therapy. If any Grade of ILD/pneumonitis occurs, permanently discontinue crizotinib.
• Assess for signs and symptoms of neuropathy (burning, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy) periodically during therapy. Usually Grade 1.
• Monitor ECG periodically during therapy in patients with HF, bradyarrhythmias, electrolyte imbalances, or taking medications that may prolong QT interval. If QTc interval >500 msec on at least 2 separate ECGs, hold until recovery to baseline or to a QTc interval <481 msec; then resume at next lower dose. If QTc interval >500 msec or 60 msec change from baseline with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently discontinue crizotinib. If symptomatic bradycardia occurs, hold dose until HR returns to 60 bpm for adults, 91 bpm for 1–<2 yr, 82 bpm for 2–3 yr, 72 bpm for 4–5 yr, 64 bpm for 6–8 yr, or 60 bpm for >8 yr. Evaluate concomitant medications; if contributing medication is identified and dose reduced or discontinued, return to previous dose of crizotinib once HR 60 bpm and/or bradycardia is asymptomatic. If no contributing medication is identified or dose modifications are not made, resume crizotinib at a reduced dose once HR 60 bpm and/or bradycardia is asymptomatic. If bradycardia is life-threatening and no contributing medication identified, discontinue crizotinib. If contributing medication is identified and dose is ↓ or discontinued, for adults, ↓ crizotinib dose to 250 mg once daily with frequent monitoring once heart rate 60 bpm and/or bradycardia is asymptomatic; for pediatrics and young adults, resume at 2nd reduction level.
• Obtain baseline and follow-up ophthalmologic examinations, including retinal examination, within 1 mo of starting therapy and every 3 mo thereafter in pediatric and young adult patients with anaplastic large cell lymphoma or pediatric patients with inflammatory myofibroblastic tumor. If visual symptoms Grade 1 (mild symptoms) or Grade 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living), monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disorders. If visual loss (Grade 3 or 4 ocular disorder, marked decrease in vision) occurs, hold crizotinib pending evaluation of severe visual loss. For Grade 3 or 4 ocular disorders, with no other cause found on evaluation, permanently discontinue crizotinib. Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography, and other evaluations as appropriate for new onset of severe visual loss.
• Monitor for signs and symptoms of GI toxicity (diarrhea, nausea, vomiting, stomatitis) during therapy. If Grade 3 nausea (inadequate oral intake for >3 days, intervention required) occurs, hold crizotinib until resolved; then resume at next lower dose. If Grade 3 vomiting (>6 episodes in 24 hr for >3 days, intervention required [tube feeding or hospitalization]) or Grade 4 vomiting (life-threatening consequences, urgent intervention indicated) occurs, hold crizotinib until resolved; then resume at next lower dose level. If Grade 3 diarrhea (increase of 7 stools per day over baseline; incontinence; hospitalization indicated) or Grade 4 (life-threatening consequences, urgent intervention indicated) occurs, hold crizotinib until resolved; then resume at next lower dose level.
• Monitor hydration status. Consider IV or oral hydration for patients at risk of dehydration, and replace electrolytes as clinically indicated.

• Test patient for ALK or ROS1 positivity in tumor specimens through an FDA-approved test (www.fda.gov/companiondiagnostics) prior to starting therapy.
  • Verify negative pregnancy test prior to starting therapy.
  • Monitor CBC with differential weekly for the 1st mo and then monthly and as clinically indicated; more frequently if Grade 3 or 4 toxicities occur. Adults:If ANC <0.5 × 10⁹/L and 1st occurrence, hold dose until ANC recovery to 1.0 × 10⁹ /L; then resume at the next lower dose. If 2nd occurrence, permanently discontinue crizotinib if patient develops febrile neutropenia or infection. For uncomplicated Grade 4 neutropenia, permanently discontinue crizotinib or hold dose until ANC recovery to 1.0 × 10⁹ /L; then resume at next lower dose. If platelet count 25–50 × 10⁹/L, hold crizotinib until recovery to platelet count >50 × 10⁹ /L and bleeding resolves; then resume at same dose. If platelet count <25 × 10⁹/L, hold crizotinib until recovery to platelet count >50 × 10⁹ /L; then resume at next lower dose. Permanently discontinue crizotinib for recurrence. If Hgb <8 g/dL, hold crizotinib until recovery to Hgb 8 g/dL; then resume at same dose. If anemia is life-threatening and urgent intervention needed, hold crizotinib until recovery to Hgb 8 g/dL; then resume at next lower dose. Permanently discontinue crizotinib for recurrence.Pediatric and Young Adults: If ANC < 0.5 × 10⁹ /L,1st occurrence: hold crizotinib until ANC > 1.0 × 10⁹ /L; then resume at the next lower dose. 2nd occurrence: Permanently discontinue crizotinib for recurrence complicated by febrile neutropenia or infection. For uncomplicated Grade 4 neutropenia, either permanently discontinue crizotinib or hold until recovery to ANC > 1.0 × 10⁹ /L; then resume at the next lower dose. If platelet count 25–50 × 10⁹ /L with concurrent bleeding,hold crizotinib until platelet count > 50 × 10⁹ /L and bleeding resolves; then resume at the same dose. If platelet count < 25 × 10⁹ /L, hold crizotinib until platelet count > 50 x 10⁹ /L; then resume at the next lower dose. Permanently discontinue crizotinib for recurrence. If Hgb < 8 g/dL,hold crizotinib until Hgb 8 g/dL; then resume at the same dose. If life-threatening anemia occurs, hold crizotinib until Hgb 8 g/dL; then resume at next lower dose. Permanently discontinue crizotinib for recurrence.
  • Monitor liver function tests every 2 wk during first 2 mo, then monthly, and as clinically indicated; more frequently if Grade 2, 3, 4 abnormalities occur. Adults:If ALT or AST ↑ >5 times ULN with total bilirubin 1.5 times ULN, hold crizotinib until recovery to baseline or 3 times ULN; then resume at next lower dose. If ALT or AST ↑ >3 times ULN with concurrent total bilirubin ↑ >1.5 times ULN (in the absence of cholestasis or hemolysis), permanently discontinue crizotinib. If Grade 3 or 4 AST or ALT ↑ with Grade 1 total bilirubin occurs, hold crizotinib until recovery to Grade 1 or baseline; then resume at 200 mg twice daily. Pediatric and Young Adults:If ALT or AST > 5 times ULN with total bilirubin 1.5 times ULN,hold crizotinib until recovery to baseline or 3 times ULN; then resume at next lower dose. If ALT or AST > 3 times ULN with total bilirubin > 1.5 times ULN (in the absence of cholestasis or hemolysis), permanently discontinue crizotinib.

• Recommended dose reductions:Adults1st dose reduction, 200 mg twice daily. 2nd dose reduction, 250 mg once daily. If unable to tolerate 250 mg of crizotinib once daily, permanently discontinue crizotinib. Pediatric and Young AdultsBSA 0.38–0.46 m², 1st dose reduction: 90 mg twice daily. 2nd dose reduction: 70 mg twice daily.BSA 0.47–0.51 m², 1st dose reduction: 100 mg twice daily. 2nd dose reduction: 80 mg twice daily.BSA 0.52–0.61 m², 1st dose reduction: 120 mg twice daily. 2nd dose reduction: 90 mg twice daily.BSA 0.62–0.80 m², 1st dose reduction: 150 mg twice daily. 2nd dose reduction: 120 mg twice daily. BSA 0.81–0.97 m², 1st dose reduction: 200 mg twice daily. 2nd dose reduction: 150 mg twice daily. BSA 0.98–1.16 m², 1st dose reduction: 220 mg twice daily. 2nd dose reduction: 170 mg twice daily. BSA 1.17–1.69 m², 1st dose reduction: 250 mg twice daily. 2nd dose reduction: 200 mg twice daily. BSA 1.70 m², 1st dose reduction: 400 mg twice daily. 2nd dose reduction: 250 twice daily. Discontinue permanently in any patient unable to tolerate two dose reductions.
• Antiemetics are recommended before and during therapy. May require antidiarrheal therapy.
• PO: Administer twice daily without regard to food. DNC: Swallow capsules whole, do not chew, crush, or split.
• Oral pellets are contained within a hard gelatin capsule. DNC: Do not chew, crush, or swallow these capsules. These particular capsules should be opened, and the contents (oral pellets) can either be emptied directly into the patient's mouth or placed into a dosing cup/spoon and then administered to the patient directly into the mouth. Once medication is administered, give patient an adequate amount of water to ensure the medication is swallowed.

• Instruct patient to take crizotinib as directed; do not change dose or stop taking without consulting health care professional. If vomiting occurs, do not take extra dose; just take next dose at regular scheduled time. Take missed doses as soon as remembered unless <6 hr until next dose. If <6 hr to next dose, skip dose and return to regular schedule; do not double doses. Advise patient to read the Patient Information before starting and with each Rx refill in case of changes.
• Advise patient to avoid eating grapefruit or drinking grapefruit juice during therapy.
• Caution patient that dizziness and visual disorders may occur. Advise patient to avoid driving or other activities requiring alertness until response to medication is known. Visual disturbances generally start within 2 wk of therapy. Instruct patient to notify health care professional if flashes of light, blurry vision, light sensitivity, or new or worse vitreous floaters occur; ophthalmological evaluation should be considered.
• Advise patient to notify health care professional immediately if signs and symptoms of liver problems (weakness, fatigue, anorexia, nausea, vomiting, abdominal pain [especially right upper quadrant abdominal pain], jaundice, dark urine, generalized pruritus, bleeding); lung problems (trouble breathing or shortness of breath, cough with or without mucus, fever); or heart problems (dizziness or fainting, abnormal heartbeats) occur.
• Inform patient that nausea, diarrhea, vomiting, and constipation are common side effects and usually occur during first few days of therapy. Standard antiemetic, antidiarrheal, and laxative medications are usually effective.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
• May cause fetal harm. Advise females of reproductive potential to use effective contraception and to avoid breastfeeding during and for 45 days following last dose of therapy. Advise males with female partners of reproductive potential to use condoms during treatment and for 90 days after final dose. May cause reduced fertility in females and males of reproductive potential; may be irreversible.

• Decreased spread of non-small cell lung cancer.
• Decreased spread of systemic anaplastic large cell lymphoma or inflammatory myofibroblastic tumor.

Xalkori