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Crizotinib

Pronunciation

(kriz OH ti nib)

Index Terms

  • C-Met/Hepatocyte Growth Factor Receptor Tyrosine Kinase Inhibitor PF-02341066
  • C-Met/HGFR Tyrosine Kinase Inhibitor PF-02341066
  • MET Tyrosine Kinase Inhibitor PF-02341066
  • PF-02341066

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Xalkori: 200 mg, 250 mg

Brand Names: U.S.

  • Xalkori

Pharmacologic Category

  • Antineoplastic Agent, Anaplastic Lymphoma Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Tyrosine kinase receptor inhibitor, which inhibits anaplastic lymphoma kinase (ALK), Hepatocyte Growth Factor Receptor (HGFR, c-MET), ROS1 (c-ros), and Recepteur d’Origine Nantais (RON). ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins (eg, ALK fusion protein) which alter signaling and expression and result in increased cellular proliferation and survival in tumors which express these fusion proteins. Approximately 2% to 7% of patients with NSCLC have the abnormal echinoderm microtubule-associated protein-like 4, or EML4-ALK gene (which has a higher prevalence in never smokers or light smokers and in patients with adenocarcinoma). Inhibition of ALK, ROS1, and c-Met phosphorylation is concentration-dependent. Crizotinib selectively inhibits ALK tyrosine kinase, which reduces proliferation of cells expressing the genetic alteration.

Distribution

Vss: 1772 L

Metabolism

Hepatic, via CYP3A4/5 (oxidation and dealkylation)

Excretion

Feces (63%; 53% as unchanged drug); urine (22%; 2% as unchanged drug)

Time to Peak

4 to 6 hours

Half-Life Elimination

Terminal: 42 hours

Protein Binding

91%

Special Populations: Renal Function Impairment

In a limited number of patients with severe renal impairment (not requiring dialysis), for a single 250 mg oral dose, the mean AUC and mean Cmax were increased 79% and 34%, respectively.

Special Populations: Hepatic Function Impairment

Hepatic impairment is likely to increase crizotinib concentrations, but crizotinib has not been studied in patients with hepatic impairment.

Use: Labeled Indications

Non-small cell lung cancer, metastatic: Treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive (as detected by an approved test) or are ROS1-positive

Contraindications

U.S. labeling: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to crizotinib or any component of the formulation; congenital long QT syndrome or with persistent Fridericia-corrected QT interval (QTcF) ≥500 msec

Dosing: Adult

Note: Crizotinib is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.

Non-small cell lung cancer (NSCLC), metastatic (ALK- or ROS1-positive): Oral: 250 mg twice daily, continue treatment until disease progression or unacceptable toxicity

Missed doses: If a dose is missed, take as soon as remembered unless it is <6 hours prior to the next scheduled dose (skip the dose if <6 hours before the next dose); do not take 2 doses at the same time to make up for a missed dose. If vomiting occurs after dose, administer the next dose at the regularly scheduled time.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 30 to 89 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute not requiring dialysis: Initial: 250 mg once daily.

Dosing: Hepatic Impairment

Hepatotoxicity prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); crizotinib undergoes extensive hepatic metabolism and systemic exposure may be increased with impairment; use with caution.

Hepatotoxicity during treatment:

Grade 3 or 4 ALT or AST elevation (ALT or AST >5 x ULN) with ≤ grade 1 total bilirubin elevation (total bilirubin ≤1.5 x ULN): Withhold treatment until recovery to baseline or ≤ grade 1 (<3 x ULN), then resume at a reduced dose (200 mg twice daily).

Recurrent grade 3 or 4 ALT or AST elevation with ≤ grade 1 total bilirubin elevation: Withhold treatment until recovery to baseline or ≤ grade 1, then resume at the next lower reduced dose (250 mg once daily).

Recurrent grade 3 or 4 ALT or AST elevation on 250 mg once daily: Permanently discontinue.

Grade 2, 3, or 4 ALT or AST elevation (ALT or AST >3 x ULN) with concurrent grade 2, 3, or 4 total bilirubin elevation (>1.5 x ULN) in the absence of cholestasis or hemolysis: Permanently discontinue.

Dosing: Adjustment for Toxicity

Note: If dose reduction is necessary, reduce dose to 200 mg orally twice daily; if necessary, further reduce to 250 mg once daily. If unable to tolerate 250 mg once daily, permanently discontinue therapy.

Hematologic toxicity (except lymphopenia, unless lymphopenia is associated with clinical events such as opportunistic infection):

Grade 3 toxicity (WBC 1,000 to 2,000/mm3, ANC 500 to 1,000/mm3, platelets 25,000 to 50,000/mm3), grade 3 anemia: Withhold treatment until recovery to ≤ grade 2, then resume at the same dose and schedule.

Grade 4 toxicity (WBC <1,000/mm3, ANC <500/mm3, platelets <25,000/mm3), grade 4 anemia: Withhold treatment until recovery to ≤ grade 2, then resume at 200 mg twice daily.

Recurrent grade 4 toxicity on 200 mg twice daily: Withhold treatment until recovery to ≤ grade 2, then resume at 250 mg once daily.

Recurrent grade 4 toxicity on 250 mg once daily: Permanently discontinue.

Nonhematologic toxicities:

Cardiovascular toxicities:

QTc prolongation:

Grade 3 QTc prolongation (QTc >500 msec without life-threatening signs or symptoms) on at least 2 separate ECGs: US labeling: Withhold treatment until recovery to baseline or to ≤ grade 1 (QTc ≤480 msec), then resume at 200 mg twice daily.

Grade 3 QTc prolongation (QTc ≥500 msec without life-threatening signs or symptoms): Canadian labeling: Withhold treatment until recovery to baseline or to ≤ grade 1 (QTc ≤470 msec), then resume at 200 mg twice daily.

Recurrent grade 3 QTc prolongation at 200 mg twice daily: Withhold treatment until recovery to baseline or to ≤ grade 1, then resume at 250 mg once daily.

Recurrent grade 3 QTc prolongation at 250 mg once daily: Permanently discontinue.

Grade 4 QTc prolongation:

US labeling: QTc >500 msec or ≥60 msec change from baseline with life-threatening symptoms: Permanently discontinue.

Canadian labeling: QTc ≥500 msec or >60 msec change from baseline with life-threatening symptoms: Permanently discontinue.

Bradycardia:

Grade 2 bradycardia (symptomatic with medical intervention indicated) or grade 3 bradycardia (severe/medically significant with intervention indicated): Withhold until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute and evaluate concomitant medications. If contributing concomitant medication is identified and discontinued (or dose adjusted), then resume crizotinib at the previous dose. If no contributing concomitant medication is identified (or cannot be discontinued or dose adjusted), resume crizotinib at a reduced dose.

Grade 4 bradycardia (life-threatening with urgent intervention indicated): Withhold until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute and evaluate concomitant medications. If contributing concomitant medication is identified and discontinued (or dose adjusted), then resume crizotinib at 250 mg once daily with frequent monitoring. If no contributing concomitant medication is identified, permanently discontinue crizotinib. Permanently discontinue for recurrence.

Hepatotoxicity: Refer to dosage adjustment in hepatic impairment.

Ocular toxicity: Visual loss (grade 4 visual disorder) or new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes): Discontinue during evaluation of severe vision loss.

Pulmonary toxicity: Interstitial lung disease (ILD)/pneumonitis (any grade; not attributable to disease progression, infection, other pulmonary disease or radiation therapy): Permanently discontinue.

Administration

Crizotinib is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.

Swallow capsules whole (do not crush, dissolve, or open capsules). Administer with or without food. If vomiting occurs after dose, administer the next dose at the regularly scheduled time.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). NIOSH recommends single gloving for administration of an intact capsule (NIOSH 2014).

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Storage

Store between 20°C and 25°C (68°F and 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alfentanil: Crizotinib may increase the serum concentration of Alfentanil. Avoid combination

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CycloSPORINE (Systemic): Crizotinib may increase the serum concentration of CycloSPORINE (Systemic). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Crizotinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Crizotinib. Avoid combination

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); Praziquantel; Vinorelbine. Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dihydroergotamine: Crizotinib may increase the serum concentration of Dihydroergotamine. Avoid combination

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification

Ergotamine: Crizotinib may increase the serum concentration of Ergotamine. Avoid combination

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: Crizotinib may increase the serum concentration of FentaNYL. Avoid combination

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Crizotinib. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant use of grapefruit products. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Nintedanib: Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Crizotinib may enhance the QTc-prolonging effect of Pimozide. Crizotinib may increase the serum concentration of Pimozide. Avoid combination

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

QuiNIDine: Crizotinib may enhance the QTc-prolonging effect of QuiNIDine. Crizotinib may increase the serum concentration of QuiNIDine. Avoid combination

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rivaroxaban: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Rivaroxaban. Management: No action is needed in patients with normal renal function. US labeling recommends avoidance in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. See monograph for details of Canadian labeling. Consider therapy modification

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Sirolimus: Crizotinib may increase the serum concentration of Sirolimus. Avoid combination

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

St John's Wort: May decrease the serum concentration of Crizotinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Tacrolimus (Systemic): Crizotinib may increase the serum concentration of Tacrolimus (Systemic). Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Edema (31% to 49%), bradycardia (5% to 15%; grades 3/4: 1%)

Central nervous system: Fatigue (27% to 29%), neuropathy (19% to 25%; includes dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), headache (22%), dizziness (18% to 22%)

Dermatologic: Skin rash (9 % to 11%)

Endocrine & metabolic: Hypophosphatemia (28% to 32%), hypokalemia (18%)

Gastrointestinal: Diarrhea (60% to 61%), nausea (55% to 56%), vomiting (46% to 47%), constipation (42% to 43%), decreased appetite (30%), abdominal pain (26%), dysgeusia (26%), dyspepsia (8% to 14%)

Genitourinary: Decreased estimated GFR (eGFR) (<90 mL/min/1.73 m2: 76%; <60 mL/min/1.73 m2: 38%; <30 mL/min/1.73 m2: 4%)

Hematologic & oncologic: Neutropenia (49% to 52%; grades 3/4: 11% to 12%), lymphocytopenia (48% to 51%; grades 3/4: 7% to 9%)

Hepatic: Increased serum ALT (76% to 79%; grades 3/4: 11% to 17%), increased serum AST (61% to 66%; grades 3/4: 6% to 9%)

Neuromuscular & skeletal: Limb pain (16%)

Ophthalmic: Visual disturbance (60% to 71%; grades 3/4: <1%; grade 4: <1%; onset: <2 weeks; includes blurred vision, diplopia, photophobia, photopsia, visual acuity decreased, visual brightness, visual field defect, visual impairment, vitreous floaters)

Respiratory: Upper respiratory tract infection (26% to 32%)

Miscellaneous: Fever (19%)

1% to 10%:

Cardiovascular: Pulmonary embolism (6%), prolonged Q-T interval on ECG (5% to 6%; grades 3/4: 2% to 3%), syncope (1% to 3%)

Endocrine & metabolic: Weight loss (10%), weight gain (8%), diabetic ketoacidosis (≤2%)

Gastrointestinal: Dysphagia (10%)

Hepatic: Hepatic failure (1%)

Infection: Sepsis (≤5%)

Neuromuscular & skeletal: Muscle spasm (8%)

Renal: Renal cyst (3% to 5%)

Respiratory: Adult respiratory distress syndrome (≤5%), interstitial pulmonary disease (≤5%; grades 3/4: 1%; includes acute respiratory distress syndrome, pneumonitis), pneumonia (≤5%), respiratory failure (≤5%), dyspnea (2%)

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, septic shock

<1% (Limited to important or life-threatening): Hepatotoxicity

Warnings/Precautions

Concerns related to adverse effects:

• Bradycardia: Symptomatic bradycardia may occur; heart rate <50 beats/minute has occurred. If possible, avoid concurrent use with other agents known to cause bradycardia (eg, beta blockers, nondihydropyridine calcium channel blockers, clonidine, digoxin). Monitor heart rate and blood pressure regularly. If symptomatic bradycardia (not life-threatening) occurs, withhold treatment until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute, evaluate concurrent medications, and potentially reduce crizotinib dose. Permanently discontinue for life-threatening bradycardia due to crizotinib; if life-threatening bradycardia occurs and concurrent medications associated with bradycardia can be discontinued or dose adjusted, restart crizotinib at a reduced dose (with frequent monitoring).

• Gastrointestinal toxicity: Crizotinib is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.

• Hepatotoxicity: Fatalities due to crizotinib-induced hepatotoxicity have occurred. Grade 3 or 4 ALT increases (usually asymptomatic and reversible) have been observed in clinical trials. May require dosage interruption and/or reduction; permanent discontinuation was necessary in some cases. Elevations in ALT or AST >5 x ULN were observed; concurrent ALT or AST elevations ≥3 x ULN and total bilirubin elevations ≥2 x ULN (without alkaline phosphatase elevations) occurred rarely. Transaminase elevation onset generally was within 2 months of treatment initiation. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of therapy, then monthly and as clinically necessary.

• Ocular toxicities: Ocular toxicities (eg, blurred vision, diplopia, photophobia, photopsia, visual acuity decreased, visual brightness, visual field defect, visual impairment, and/or vitreous floaters) commonly occur. Onset is generally within 1 week of treatment initiation. Grade 4 visual field defect with vision loss had been reported (rare); optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Discontinue with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Obtain ophthalmic evaluation (including best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography, and other evaluations as appropriate). The risks of restarting crizotinib after severe vision loss have not been evaluated; the decision to resume therapy should consider the potential benefits of treatment.

• Pulmonary toxicity: Severe, life-threatening, and potentially fatal interstitial lung disease (ILD)/pneumonitis has been associated with crizotinib. Onset was generally within 3 months of treatment initiation. Monitor for pulmonary symptoms which may indicate ILD/pneumonitis; exclude other potential causes (eg, disease progression, infection, other pulmonary disease, or radiation therapy). Permanently discontinue if treatment-related ILD/pneumonitis is confirmed.

• QT prolongation: QTc prolongation has been observed. Monitor ECG and electrolytes in patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QT interval. May require treatment interruption, dosage reduction, or discontinuation. Avoid use in patients with congenital long QT syndrome. Canadian labeling contraindicates use in patients with congenital long QT syndrome or persistent QTcF ≥500 msec.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; has not been studied; patients with ALT or AST >2.5 times ULN (>5 times ULN if due to liver metastases) and total bilirubin >1.5 times ULN were excluded from studies. Crizotinib is extensively metabolized in the liver and liver impairment is likely to increase crizotinib levels.

• Renal impairment: Reduce initial dose in patients with severe renal impairment not requiring dialysis.

Concurrent drug therapy issues:

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Avoid concomitant use with strong CYP3A4 inhibitors and inducers and with CYP3A4 substrates.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• ALK or ROS1 positivity: Approved for use only in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene or ROS1 rearrangements. The Vysis ALK break-apart FISH probe kit is approved to test for the ALK gene abnormality. An approved test is not currently available for detection of ROS1 rearrangements; in clinical trials, ROS1 positivity was determined by laboratory-developed break-apart FISH or RT-PCR.

Monitoring Parameters

ALK or ROS1 positivity; CBC with differential monthly and as clinically appropriate (monitor more frequently if grades 3 or 4 abnormalities observed or with fever or infection), liver function tests every 2 weeks for the first 2 months, then monthly and as clinically appropriate (monitor more frequently if grades 2, 3, or 4 abnormalities observed); renal function (baseline and periodic). Monitor pulmonary symptoms (for interstitial lung disease [ILD]/pneumonitis). Monitor heart rate and blood pressure; monitoring ECG and electrolytes in patients with heart failure, bradycardia, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QT interval. Obtain ophthalmic evaluation (including best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography, and other evaluations as appropriate) if severe visual loss occurs.

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Based on the mechanism of action, crizotinib may cause fetal harm if administered during pregnancy. Women of childbearing potential should use adequate contraception during treatment and for at least 45 days after the last crizotinib dose; males with female partners of reproductive potential should use condoms during treatment and for at least 90 days after the final dose. The Canadian labeling recommends adequate contraception during treatment and for at least 90 days after the last dose for both males and females.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, loss of strength and energy, nausea, vomiting, pharyngitis, rhinitis, rhinorrhea, constipation, diarrhea, abdominal pain, muscle spasms, weight gain, weight loss, headache, or change in taste. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), angina, dizziness, passing out, tachycardia, bradycardia, abnormal heartbeat, coughing up blood, shortness of breath, burning or numbness feeling, abnormal gait, muscle weakness, difficulty swallowing, bruising, bleeding, edema, blurred vision, vision loss, sensitivity to bright lights, seeing floaters, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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