Crizotinib: Drug information

(For additional information see "Crizotinib: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

Brand Names: US

Xalkori

Brand Names: Canada

Xalkori

Pharmacologic Category

Antineoplastic Agent, Anaplastic Lymphoma Kinase Inhibitor;
Antineoplastic Agent, MET Inhibitor;
Antineoplastic Agent, Tyrosine Kinase Inhibitor

Dosing: Adult

Note: Crizotinib is associated with a moderate or high emetic potential (ASCO [Hesketh 2020]); antiemetics are recommended to prevent nausea and vomiting. Provide standard antidiarrheals; consider hydration (IV or oral; if at risk for dehydration), electrolyte replacement, and nutritional support as clinically indicated.

Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory

Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory: Patients ≤21 years of age: Oral: 280 mg/m² twice daily until disease progression or unacceptable toxicity. Note: Consider IV or oral hydration for patients at risk of dehydration and replace electrolytes as needed. Antidiarrheal agents may also be necessary.

**Recommended Crizotinib Dose for Anaplastic Large Cell Lymphoma**
BSA	Recommended crizotinib dose
≥1.7 m²	500 mg twice daily
1.52 to 1.69 m²	450 mg twice daily
1.17 to 1.51 m²	400 mg twice daily
0.81 to 1.16 m²	250 mg twice daily
0.6 to 0.8 m²	200 mg twice daily

Inflammatory myofibroblastic tumor, ALK-positive, unresectable, recurrent, or refractory

Inflammatory myofibroblastic tumor, ALK-positive, unresectable, recurrent, or refractory: Oral: 250 mg twice daily until disease progression or unacceptable toxicity.

Non–small cell lung cancer, metastatic, ALK- or ROS1-positive

Non–small cell lung cancer, metastatic, ALK- or ROS1-positive: Oral: 250 mg twice daily, continue until disease progression or unacceptable toxicity (Shaw 2013; Shaw 2019; Solomon 2018).

Missed doses: If a dose is missed, administer the missed dose unless the next dose is due within 6 hours (skip the dose if <6 hours before the next dose). If vomiting occurs after dose, administer the next dose at the regularly scheduled time.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Kidney function estimated using the modified Cockcroft-Gault equation.

Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory:

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

CrCl <30 mL/minute not requiring dialysis:

BSA ≥1.7 m²: 250 mg twice daily.

BSA ≥1.17 to 1.69 m²: 200 mg twice daily.

BSA ≥0.81 to 1.16 m²: 250 mg once daily.

BSA 0.6 to 0.8 m²: Permanently discontinue crizotinib.

Inflammatory myofibroblastic tumor (ALK-positive) or non–small cell lung cancer, metastatic (ALK- or ROS1-positive):

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: Adult

Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory:

Hepatotoxicity prior to treatment initiation:

Mild impairment (AST > ULN and total bilirubin ≤ ULN or total bilirubin >1 to ≤1.5 times ULN and any AST): No dose adjustment necessary.

Moderate impairment (total bilirubin >1.5 to ≤3 times ULN and any AST):

BSA ≥1.7 m²: 400 mg twice daily.

BSA ≥1.17 to 1.69 m²: 250 mg twice daily.

BSA ≥0.81 to 1.16 m²: 200 mg twice daily.

BSA 0.6 to 0.8 m²: 250 mg once daily.

Severe impairment (total bilirubin >3 times ULN and any AST):

BSA ≥1.7 m²: 250 mg twice daily.

BSA ≥1.17 to 1.69 m²: 200 mg twice daily.

BSA ≥0.81 to 1.16 m²: 250 mg once daily.

BSA 0.6 to 0.8 m²: Permanently discontinue crizotinib.

Hepatotoxicity during treatment:

ALT or AST >5 × ULN with total bilirubin ≤1.5 × ULN: Withhold crizotinib until recovery to baseline or ≤3 × ULN, then resume at the next lower dose. Refer to "Dosing: Adjustment for Toxicity: Adult" for dosage reduction levels.

ALT or AST >3 × ULN with concurrent total bilirubin >1.5 × ULN in the absence of cholestasis or hemolysis: Permanently discontinue crizotinib.

Inflammatory myofibroblastic tumor (ALK-positive) or non–small cell lung cancer, metastatic (ALK- or ROS1-positive):

Hepatotoxicity prior to treatment initiation:

Mild impairment (AST > ULN and total bilirubin ≤ ULN or total bilirubin >1 to ≤1.5 times ULN and any AST): No dose adjustment necessary.

Moderate impairment (total bilirubin >1.5 to ≤3 times ULN and any AST): 200 mg twice daily.

Severe impairment (total bilirubin >3 times ULN and any AST): 250 mg once daily.

Hepatotoxicity during treatment:

ALT or AST >5 x ULN with total bilirubin ≤1.5 × ULN: Withhold crizotinib until recovery to baseline or ≤3 × ULN, then resume at the next lower dose.

ALT or AST >3 × ULN with concurrent total bilirubin elevation >1.5 × ULN in the absence of cholestasis or hemolysis: Permanently discontinue crizotinib.

Dosing: Obesity: Adult

American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m²: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m² experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status. If dose reduction for toxicity is recommended in the prescribing information, the dose should be increased back to the initial or previously tolerated dose only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (ASCO [Griggs 2021]).

Dosing: Adjustment for Toxicity: Adult

Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory:

**Crizotinib Dose Reduction Levels in Anaplastic Large Cell Lymphoma**
BSA	First dose reduction	Second dose reduction^a
^aPermanently discontinue crizotinib if unable to tolerate crizotinib after 2 dose reductions.
≥1.7 m²	400 mg twice daily	250 mg twice daily
1.17 to 1.69 m²	250 mg twice daily	200 mg twice daily
0.81 to 1.16 m²	200 mg twice daily	250 mg once daily
0.6 to 0.8 m²	250 mg once daily	Permanently discontinue crizotinib

**Crizotinib Dosage Modification for Adverse Reactions in Anaplastic Large Cell Lymphoma**
Adverse reaction severity	Crizotinib dose modification
Hematologic toxicities
ANC <500/mm³	1^st occurrence: Withhold crizotinib until recovery to ANC >1,000/mm³, then resume at the next lower dose.
ANC <500/mm³	2^nd occurrence: For uncomplicated grade 4 neutropenia, either withhold crizotinib until recovery to ANC >1,000/mm³then resume at the next lower dose or permanently discontinue. Permanently discontinue if unable to tolerate crizotinib after 2 dose reductions. Permanently discontinue crizotinib for recurrence complicated by febrile neutropenia or infection.
Platelets 25,000 to 50,000/mm³ with concurrent bleeding	Withhold crizotinib until platelets recover to >50,000/mm³ and bleeding resolves, then resume at the same dose.
Platelets <25,000/mm³	Withhold crizotinib until platelets recover to >50,000/mm³, then resume at the next lower dose. Permanently discontinue for recurrence.
Hemoglobin <8 g/dL	Withhold crizotinib until hemoglobin recovers to ≥8 g/dL, then resume at the same dose.
Life-threatening anemia; urgent intervention indicated	Withhold crizotinib until hemoglobin recovers to ≥8 g/dL, then resume at the next lower dose. Permanently discontinue for recurrence.
Cardiac effects
QTc >500 msec on at least 2 separate ECGs	Withhold crizotinib until recovery to QTc <481 msec or baseline, then resume at the next lower dose.
QTc >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.
Symptomatic bradycardia (heart rate <60 beats/minute), may be severe and medically significant with medical intervention indicated	Withhold until recovery to a resting heart rate of ≥60 beats/minute.
Life-threatening bradycardia 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 is dose adjusted), then (upon recovery) resume crizotinib at the 2^nd dose reduction (see previous table) with frequent monitoring. If no contributing concomitant medication is identified, permanently discontinue crizotinib. Permanently discontinue for recurrence.
GI toxicity
Nausea, grade 3 (inadequate oral intake for >3 days, medical intervention required)	Maximize medical management. If grade 3 nausea persists, withhold crizotinib until resolved, then resume at the next lower dose. Permanently discontinue if unable to tolerate crizotinib after 2 dose reductions.
Vomiting, grade 3 (>6 episodes in 24 hours for >3 days, medical intervention, such as tube feeding or hospitalization required), or grade 4 (life-threatening consequences, urgent intervention required)	Maximize medical management. If grade 3 or 4 vomiting persists, withhold crizotinib until resolved, then resume at the next lower dose. Permanently discontinue if unable to tolerate crizotinib after 2 dose reductions.
Diarrhea, grade 3 (increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated, or grade 4 (life-threatening consequences, urgent intervention required)	Maximize medical management. If grade 3 or 4 diarrhea persists, withhold crizotinib until resolved, then resume at the next lower dose. Permanently discontinue if unable to tolerate crizotinib after 2 dose reductions.
Ocular toxicity, including visual loss
Visual symptoms, grade 1 (mild symptoms) or grade 2 (moderate symptoms affecting ability to perform activities of daily living)	Monitor; report any symptoms to an ophthalmic specialist. Consider dose reduction for grade 2 visual disorders.
Visual loss (grade 3 or 4 ocular disorder, marked decrease in vision)	Withhold crizotinib pending evaluation. Permanently discontinue crizotinib for grade 3 or 4 ocular disorders (if no other etiology is identified).
New onset of severe visual loss (best corrected vision <20/200 in one or both eyes)	Discontinue crizotinib during evaluation of severe vision loss (decision to resume crizotinib should consider potential benefits versus risks).
Pulmonary toxicity
Drug-related interstitial lung disease/pneumonitis (any grade)	Permanently discontinue crizotinib.

Inflammatory myofibroblastic tumor (ALK-positive) or non–small cell lung cancer, metastatic (ALK- or ROS1-positive):

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 crizotinib.

**Crizotinib Dosage Modification for Adverse Reactions in Inflammatory Myofibroblastic Tumor or Non–Small Cell Lung Cancer**
Adverse reaction severity	Crizotinib dose modification
^aExcept lymphopenia (unless associated with clinical events [eg, opportunistic infections]).
Hematologic toxicity^a
Grade 3 hematologic toxicity^a	Withhold crizotinib until recovery to grade ≤2, then resume at the same dose.
Grade 4 hematologic toxicity^a	Withhold crizotinib until recovery to grade ≤2, then resume at the next lower dose.
Cardiac effects
QTc >500 msec on at least 2 separate ECGs	Withhold crizotinib until recovery to QTc <481 msec or baseline, then resume at the next lower dose.
QTc >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.
Symptomatic bradycardia (heart rate <60 beats/minute), may be severe and medically significant with medical intervention indicated	Withhold crizotinib until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute and evaluate concomitant medications associated with bradycardia and antihypertensives. If contributing concomitant medication is identified and discontinued (or is dose adjusted), then (upon recovery) resume crizotinib at the previous dose. If no contributing concomitant medication is identified (or cannot be discontinued or dose adjusted), then (upon recovery) resume crizotinib at a reduced dose.
Life-threatening bradycardia with urgent intervention indicated	Withhold crizotinib 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 (upon recovery) resume crizotinib at 250 mg once daily with frequent monitoring. If no contributing concomitant medication is identified, permanently discontinue crizotinib. Permanently discontinue for recurrence.
Ocular toxicity
Visual loss (grade 4 ocular disorder) or new onset of severe visual loss (best corrected vision <20/200 in one or both eyes)	Discontinue crizotinib during evaluation of severe vision loss (decision to resume crizotinib should consider potential benefits versus risks).
Pulmonary toxicity
Any grade drug-related interstitial lung disease/pneumonitis	Permanently discontinue crizotinib.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Crizotinib: Pediatric drug information")

Dosage guidance:

Clinical considerations: Crizotinib is associated with a moderate or high emetic potential (ASCO [Hesketh 2020]); antiemetics are recommended to prevent nausea and vomiting. Provide standard antidiarrheals; consider hydration (IV or oral; if at risk for dehydration), electrolyte replacement, and nutritional support as clinically indicated.

Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory

Anaplastic large cell lymphoma (ALCL), systemic ALK-positive, relapsed or refractory:

Note: May require combining capsule strengths to achieve dose. Consider IV or oral hydration for patients at risk of dehydration and replace electrolytes as needed; antidiarrheal agents may be necessary for GI toxicities.

BSA-directed dosing: Children and Adolescents: Oral: 280 mg/m² twice daily; maximum dose: 500 mg/dose; continue until disease progression or unacceptable toxicity.

Fixed dosing (BSA-banded):

Children and Adolescents: Oral: Administer dose based on BSA-band in the following table; continue until disease progression or unacceptable toxicity. Some dosage forms may not be appropriate for use in all patients. Oral pellets available in multiple strengths and may be combined to achieve individual doses; however, no more than 4 oral pellet shells may be used for a single dose.

**Dose for** **ALCL in Children and Adolescents**
BSA band	Recommended crizotinib dose (mg) to achieve 280 mg/m² twice daily
0.38 to 0.46 m²	120 mg twice daily
0.47 to 0.51 m²	140 mg twice daily
0.52 to 0.61 m²	150 mg twice daily
0.62 to 0.8 m²	200 mg twice daily
0.81 to 0.97 m²	250 mg twice daily
0.98 to 1.16 m²	300 mg twice daily
1.17 to 1.33 m²	350 mg twice daily
1.34 to 1.51 m²	400 mg twice daily
1.52 to 1.69 m²	450 mg twice daily
≥1.7 m²	500 mg twice daily

Inflammatory myofibroblastic tumor, ALK-positive, unresectable, recurrent, or refractory

Inflammatory myofibroblastic tumor (IMT), ALK-positive, unresectable, recurrent, or refractory:

BSA-directed dosing: Children and Adolescents: Oral: 280 mg/m² twice daily; maximum dose: 500 mg/dose; continue until disease progression or unacceptable toxicity.

Fixed dosing (BSA-banded):

**Dose for IMT** **in Children and Adolescents**
BSA band	Recommended crizotinib dose (mg) to achieve 280 mg/m² twice daily
0.38 to 0.46 m²	120 mg twice daily
0.47 to 0.51 m²	140 mg twice daily
0.52 to 0.61 m²	150 mg twice daily
0.62 to 0.8 m²	200 mg twice daily
0.81 to 0.97 m²	250 mg twice daily
0.98 to 1.16 m²	300 mg twice daily
1.17 to 1.33 m²	350 mg twice daily
1.34 to 1.51 m²	400 mg twice daily
1.52 to 1.69 m²	450 mg twice daily
≥1.7 m²	500 mg twice daily

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity:

Anaplastic large cell lymphoma (ALCL) or Inflammatory myofibroblastic tumor (IMT):

Children and Adolescents: Oral:

**Dosage Adjustment for Crizotinib Toxicity ALCL or IMT in Children and Adolescents**
BSA	First dose reduction	Second dose reduction^a
^a Permanently discontinue crizotinib if unable to tolerate crizotinib after 2 dose reductions.
0.38 to 0.46 m²	90 mg twice daily	70 mg twice daily
0.47 to 0.51 m²	100 mg twice daily	80 mg twice daily
0.52 to 0.61 m²	120 mg twice daily	90 mg twice daily
0.62 to 0.8 m²	150 mg twice daily	120 mg twice daily
0.81 to 0.97 m²	200 mg twice daily	150 mg twice daily
0.98 to 1.16 m²	220 mg twice daily	170 mg twice daily
1.17 to 1.33 m²	250 mg twice daily	200 mg twice daily
1.34 to 1.69 m²	250 mg twice daily	200 mg twice daily
≥1.7 m²	400 mg twice daily	250 mg twice daily

**Hematologic Toxicities**
Adverse reaction	Crizotinib dose adjustment
ANC <500/mm³	1^st occurrence: Withhold crizotinib until recovery to ANC >1,000/mm³, then resume at the next lower dose.
ANC <500/mm³	2^nd occurrence: For uncomplicated grade 4 neutropenia, either withhold crizotinib until recovery to ANC >1,000/mm³then resume at the next lower dose or permanently discontinue. Permanently discontinue crizotinib for recurrence complicated by febrile neutropenia or infection.
Platelets 25,000 to 50,000/mm³ with concurrent bleeding	Withhold crizotinib until recovery to >50,000/mm³ and bleeding resolves, then resume at the same dose.
Platelets <25,000/mm³	Withhold crizotinib until recovery to >50,000/mm³, then resume at the next lower dose. Permanently discontinue for recurrence.
Hemoglobin <8 g/dL	Withhold crizotinib until recovery to ≥8 g/dL, then resume at the same dose.
Anemia, life-threatening; urgent intervention indicated	Withhold crizotinib until recovery to ≥8 g/dL, then resume at the next lower dose. Permanently discontinue for recurrence.

**Nonhematologic Toxicities**
Adverse reaction	Crizotinib dose adjustment
Cardiac effects
QTc >500 msec on at least 2 separate ECGs	Withhold crizotinib until recovery to QTc <481 msec or baseline, then resume at the next lower dose.
QTc >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.
Bradycardia; symptomatic, may be severe and medically significant with medical intervention indicated	Withhold until recovery to the following age-dependent resting heart rate (based on 2.5^th percentile per age-specific norms): 1 to <2 years: ≥91 bpm 2 to <4 years: ≥82 bpm 4 to <6 years: ≥72 bpm 6 to ≤8 years: ≥64 bpm >8 years: ≥60 bpm
Bradycardia; life-threatening with urgent intervention indicated	Withhold until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute and evaluate for contributing concomitant medications. • If contributing concomitant medication is identified and discontinued (or dose adjusted), then resume crizotinib at the 2^nd dose reduction (see previous table) with frequent monitoring. • If no contributing concomitant medication is identified, permanently discontinue crizotinib.
	If life-threatening bradycardia recurs, permanently discontinue.
GI toxicity
Nausea, grade 3	Maximize medical management. If grade 3 nausea persists, withhold crizotinib until resolved, then resume at the next lower dose.
Nausea, grade 3	Permanently discontinue if unable to tolerate crizotinib after 2 dose reductions.
Vomiting, grade 3 or grade 4	Maximize medical management. If grade 3 or 4 vomiting persists, withhold crizotinib until resolved, then resume at the next lower dose.
Vomiting, grade 3 or grade 4	Permanently discontinue if unable to tolerate crizotinib after 2 dose reductions.
Diarrhea, grade 3 or grade 4	Maximize medical management. If grade 3 or 4 diarrhea persists, withhold crizotinib until resolved, then resume at the next lower dose.
Diarrhea, grade 3 or grade 4	Permanently discontinue if unable to tolerate crizotinib after 2 dose reductions.
Ocular toxicity, including visual loss
Visual symptoms, grade 1 or grade 2	Monitor, and report symptoms to an ophthalmic specialist. Consider dose reduction for grade 2 visual disorders.
Visual loss, grade 3 or 4	Withhold crizotinib pending evaluation. Permanently discontinue crizotinib for grade 3 or 4 ocular disorders (if no other etiology is identified).
Pulmonary toxicity
Any grade drug-related interstitial lung disease (ILD)/pneumonitis	Permanently discontinue crizotinib.

Dosing: Kidney Impairment: Pediatric

Anaplastic large cell lymphoma (ALCL) or Inflammatory myofibroblastic tumor (IMT):

Altered Kidney Function:

Note: Kidney function is estimated using the Schwartz equation in pediatric patients.

Children and Adolescents: Oral:

**Crizotinib Dosing for Altered Kidney Function for ALCL or IMT in Children and Adolescents**
BSA	Mild to moderate renal impairment (CrCl ≥30 mL/minute/1.73 m²)	Severe renal impairment (CrCl <30 mL/minute/1.73 m²) not requiring dialysis
0.38 to 0.46 m²	No adjustment necessary	70 mg twice daily
0.47 to 0.51 m²		80 mg twice daily
0.52 to 0.61 m²		90 mg twice daily
0.62 to 0.8 m²		120 mg twice daily
0.81 to 0.97 m²		150 mg twice daily
0.98 to 1.16 m²		170 mg twice daily
1.17 to 1.33 m²		200 mg twice daily
1.34 to 1.69 m²		200 mg twice daily
≥1.7 m²		250 mg twice daily

Dosing: Hepatic Impairment: Pediatric

Anaplastic large cell lymphoma (ALCL) or Inflammatory myofibroblastic tumor (IMT):

Children and Adolescents: Oral:

Baseline hepatic impairment:

**Crizotinib Dosing for Patients With Baseline Hepatic Impairment for ALCL or IMT in Children and Adolescents**
Body surface area	Mild hepatic impairment	Moderate impairment (any AST and a total bilirubin >1.5 times ULN and ≤3 times ULN)	Severe impairment (any AST and a total bilirubin >3 times ULN)
0.38 to 0.46 m²	No adjustment necessary	90 mg twice daily	70 mg twice daily
0.47 to 0.51 m²		100 mg twice daily	80 mg twice daily
0.52 to 0.61 m²		120 mg twice daily	90 mg twice daily
0.62 to 0.8 m²		150 mg twice daily	120 mg twice daily
0.81 to 0.97 m²		200 mg twice daily	150 mg twice daily
0.98 to 1.16 m²		220 mg twice daily	170 mg twice daily
1.17 to 1.33 m²		250 mg twice daily	200 mg twice daily
1.34 to 1.69 m²		250 mg twice daily	200 mg twice daily
≥1.7 m²		400 mg twice daily	250 mg twice daily

Hepatotoxicity during treatment:

ALT or AST >5 times ULN with total bilirubin ≤1.5 times ULN: Withhold treatment until recovery to baseline or ≤3 times ULN, then resume at the next lower dose based on dosage reduction level tables.

ALT or AST >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN in the absence of cholestasis or hemolysis: Permanently discontinue crizotinib.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

>10%:

Cardiovascular: Bradycardia (5% to 14%), edema (31% to 49%)

Dermatologic: Skin rash (9% to 11%)

Endocrine & metabolic: Hypokalemia (18%), hypophosphatemia (28% to 32%)

Gastrointestinal: Abdominal pain (26%), constipation (42% to 43%), decreased appetite (27% to 30%), diarrhea (60% to 61%; grades 3/4: 2%), dysgeusia (26%), dyspepsia (8% to 14%), nausea (55% to 56%; grades 3/4: 1%), vomiting (46% to 47%; grades 3/4: 1% to 2%)

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

Hepatic: Increased serum alanine aminotransferase (76% to 79%), increased serum aspartate aminotransferase (61% to 66%)

Nervous system: Dizziness (18% to 22%), fatigue (27% to 29%), headache (22%), neuropathy (19% to 25%; including abnormal gait, abnormal sensory symptoms, burning sensation of skin, dysesthesia, hypoesthesia, myasthenia, neuralgia, paresthesia, peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy)

Neuromuscular & skeletal: Limb pain (16%)

Ophthalmic: Visual disturbance (60% to 71%; onset: <1 week; including blurred vision, decreased visual acuity, diplopia, photophobia, photopsia, vision loss, visual field defect, vitreous opacity)

Renal: 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%), increased serum creatinine (96% to 99%)

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

Miscellaneous: Fever (19%)

1% to 10%:

Cardiovascular: Prolonged QT interval on ECG (5% to 6%), pulmonary embolism (6%), syncope (1% to 3%)

Endocrine & metabolic: Decreased plasma testosterone (1%; hypogonadism), weight gain (8%), weight loss (10%)

Gastrointestinal: Dysphagia (10%), esophagitis (2% to 6%)

Hepatic: Hepatic failure (1%)

Neuromuscular & skeletal: Muscle spasm (8%)

Renal: Renal cyst (3% to 5%)

Respiratory: Interstitial pulmonary disease (1% to 4%; including acute respiratory distress syndrome, pneumonitis)

<1%:

Dermatologic: Skin photosensitivity

Hepatic: Hepatotoxicity

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, septic shock

Endocrine & metabolic: Diabetic ketoacidosis

Infection: Sepsis

Respiratory: Dyspnea (including severe dyspnea), pneumonia, respiratory failure (including acute respiratory failure)

Postmarketing: Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

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

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular toxicity: Symptomatic bradycardia may occur; grade 3 bradycardia has been observed (rare). Grade 3 syncope has been reported. When possible, avoid concurrent use with other agents known to cause bradycardia (eg, beta blockers, nondihydropyridine calcium channel blockers, clonidine, digoxin). QT prolongation may occur; QTcF ≥500 msec has been reported. Avoid crizotinib in patients with congenital long QT syndrome.

• GI toxicity: GI toxicity occurs in the majority of patients; grade 3 diarrhea, nausea, vomiting, and stomatitis have been reported. Provide standard antiemetics and antidiarrheals. Consider supportive care, such as hydration, electrolyte supplementation, and nutritional support as necessary.

• Hepatotoxicity: Fatalities due to crizotinib-induced hepatotoxicity have occurred with crizotinib. Elevations in ALT or AST >5 × ULN were observed; concurrent ALT or AST elevations ≥3 × ULN and total bilirubin elevations ≥2 × ULN (without alkaline phosphatase elevations) occurred rarely. Transaminase elevation onset generally was within 2 months of treatment initiation.

• Ocular toxicities: Visual disorders commonly occur with crizotinib. The most common visual symptoms were blurred vision and visual impairment. Grade 3 myopic optic nerve disorder has been observed and 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. 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. In patients with non–small cell lung cancer (NSCLC), the onset was generally within 3 months of treatment initiation.

Other warnings/precautions:

• ALK or ROS1 positivity: Approved for use in patients with metastatic NSCLC who test positive for the abnormal ALK gene or ROS1 rearrangements, in pediatric and adult patients with ALK-positive unresectable/recurrent/refractory inflammatory myofibroblastic tumor, as well as in pediatric patients and young adults with ALK-positive anaplastic large cell lymphoma. Information on approved tests for ALK and ROS1 rearrangements in NSCLC may be found at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.

• Photosensitivity: Patients should avoid prolonged sun exposure, wear protective clothing, and use a broad-spectrum sunscreen and lip balm during treatment.

Product Availability

Xalkori oral pellets: FDA approved September 2023; anticipated availability currently unknown. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.

Dosage Forms: US

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

Capsule, Oral:

Xalkori: 200 mg, 250 mg

Capsule Sprinkle, Oral:

Xalkori: 20 mg, 50 mg, 150 mg

Generic Equivalent Available: US

Pricing: US

Capsule, sprinkles (Xalkori Oral)

20 mg (per each): $44.85

50 mg (per each): $105.79

150 mg (per each): $317.37

Capsules (Xalkori Oral)

200 mg (per each): $448.55

250 mg (per each): $448.55

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Dosage Forms: Canada

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

Capsule, Oral:

Xalkori: 200 mg, 250 mg

Prescribing and Access Restrictions

Available through specialty pharmacies. Further information may be obtained from the manufacturer, Pfizer, at 1-877-744-5675, or at http://www.pfizerpro.com

Administration: Adult

Crizotinib is associated with a moderate or high emetic potential (ASCO [Hesketh 2020]); antiemetics are recommended to prevent nausea and vomiting.

Oral: Swallow capsules whole. Administer with or without food. If vomiting occurs after dose, administer the next dose at the regularly scheduled time.

Patients unable to swallow whole capsules: Capsules may be dissolved using the following method (manufacturer data on file February 2021; not formally evaluated in pharmacokinetic studies):

Prepare ~240 mL of boiling water (tap or bottled). Pour 15 mL of boiling water into a drinking glass, add unopened crizotinib capsule(s) containing dose to the water, stir continuously with a spoon for ≥2 minutes, add another 15 mL of the boiling water to drinking glass, stir continuously with the spoon for 2 minutes, add 15 mL of room temperature or cold water to the solution (while pouring into glass, use this water to also rinse the stirring spoon), swirl vigorously for 10 seconds, and administer to patient immediately (preparation is stable for 2 hours). To ensure entire dose consumed, add 15 mL room temperature water to drinking glass, rinsing sides in process; swirl vigorously for 10 seconds and administer immediately. Repeat rinse of drinking glass with water and administration 2 more times. Note: To mask unpleasant taste, mint-flavored candy may be dissolved in the patient's mouth while preparing dose; remove any undissolved mint from the patient's mouth prior to dose administration.

Administration: Pediatric

Note: Crizotinib is associated with a moderate emetic potential (ASCO [Hesketh 2020]); antiemetics should be offered.

Oral: Administer with or without food. If vomiting occurs after dose, administer the next dose at the regularly scheduled time.

Capsules: Swallow capsules whole; do not chew, crush, or split.

Patients unable to swallow capsules whole: Capsules may be dissolved using the following method (manufacturer data on file February 2021; not formally evaluated in pharmacokinetic studies):

1. Prepare 236 mL (1 cup) of boiling water (tap or bottled). Pour 15 mL of the boiling water into a drinking glass, add unopened crizotinib capsule(s) containing dose to the water, stir continuously with spoon for ≥2 minutes, add another 15 mL of the boiling water to drinking glass, stir solution continuously for 2 minutes, add 15 mL of room temperature or cold water to the solution (while pouring into glass, use this water to also rinse the stirring spoon), swirl vigorously for 10 seconds, and administer to patient immediately (stable for 2 hours).

To mask unpleasant taste, mint-flavored candy may be dissolved in the patient's mouth while dose being prepared (if developmentally appropriate); any undissolved mint should be removed from the patient's mouth prior to dose administration.

2. To ensure entire dose consumed, add 15 mL room temperature water to drinking glass, rinsing sides in process; stir vigorously for 10 seconds and administer immediately, and repeat rinse of drinking glass with water and administration 2 more times.

Oral pellets: Pellets are encapsulated within shells; no more than 4 oral pellet shells should be used for a single dose. Oral pellets are available in multiple strengths which may be combined for a dose. Administer by either opening the shells and emptying contents directly into the patient's mouth or opening shells and emptying contents into an oral dosing aid (eg, spoon, medicine cup) and then administering pellets via the dosing aid directly into the patient's mouth. Immediately after administration, patient should drink a sufficient amount of water to ensure all medication is swallowed.

Missed doses: If a dose is missed, take as soon as remembered unless the next dose is due within 6 hours, then missed dose should be skipped; do not take 2 doses at the same time to make up for a missed dose.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202570s036lbl.pdf#page=41, must be dispensed with this medication.

Use: Labeled Indications

Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory: Treatment of relapsed or refractory systemic anaplastic large cell lymphoma (ALK-positive) in pediatric patients ≥1 year of age and young adults.

Limitations of use: Safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory systemic ALK-positive anaplastic large cell lymphoma.

Inflammatory myofibroblastic tumor, ALK-positive, unresectable, recurrent, or refractory: Treatment of ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumor in adult and pediatric patients ≥1 year of age.

Non–small cell lung cancer, metastatic, ALK- or ROS1-positive: Treatment of metastatic non–small cell lung cancer in patients whose tumors are ALK-positive or are ROS1-positive (as detected by an approved test).

Medication Safety Issues

Sound-alike/look-alike issues:

Crizotinib may be confused with afatinib, alectinib, brigatinib, cabozantinib, capmatinib, ceritinib, cobimetinib, copanlisib, crizanlizumab, erlotinib, gefitinib, lorlatinib, PONATinib, tepotinib.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (moderate)

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib. Management: Monitor for increased abemaciclib toxicities if combined with moderate CYP3A4 inhibitors. Consider reducing the abemaciclib dose in 50 mg decrements if necessary. Risk C: Monitor therapy

Acalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Risk D: Consider therapy modification

ALfentanil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ALfentanil. Management: If use of alfentanil and moderate CYP3A4 inhibitors is necessary, consider dosage reduction of alfentanil until stable drug effects are achieved. Frequently monitor patients for respiratory depression and sedation when these agents are combined. Risk D: Consider therapy modification

Alfuzosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alfuzosin. Risk C: Monitor therapy

Alitretinoin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alitretinoin (Systemic). Risk C: Monitor therapy

ALPRAZolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ALPRAZolam. Management: Consider alternatives to this combination when possible. If combined, consider an alprazolam dose reduction and monitor for increased alprazolam effects and toxicities (eg, sedation, lethargy). Risk D: Consider therapy modification

Amiodarone: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Amiodarone. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy

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

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

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Risk X: 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, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor therapy

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

Atogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atogepant. Risk C: Monitor therapy

Atorvastatin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy

Avacopan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avacopan. Risk C: Monitor therapy

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil 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 (eg, hypotension, syncope, priapism). Risk D: Consider therapy modification

Avapritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avapritinib. Management: Avoid use of moderate CYP3A4 inhibitors with avapritinib. If this combination cannot be avoided, reduce the avapritinib dose to 100 mg daily for the treatment of GIST or to 50 mg daily for the treatment of advanced systemic mastocytosis. Risk D: Consider therapy modification

Axitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Axitinib. Risk C: Monitor therapy

Barnidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Barnidipine. Risk C: Monitor therapy

Benidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benidipine. Risk C: Monitor therapy

Benzhydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased. Risk C: Monitor therapy

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

Bortezomib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bortezomib. Risk C: Monitor therapy

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

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

Brigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Oral Inhalation). Risk C: Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Management: Avoid the concomitant use of CYP3A4 inhibitors and oral budesonide. If patients receive both budesonide and CYP3A4 inhibitors, they should be closely monitored for signs and symptoms of corticosteroid excess. Risk D: Consider therapy modification

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

Buprenorphine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Buprenorphine. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of BusPIRone. Risk C: Monitor therapy

Cabozantinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cabozantinib. Risk C: Monitor therapy

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

Capivasertib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Capivasertib. Management: If capivasertib is combined with moderate CYP3A4 inhibitors, reduce the capivasertib dose to 320 mg twice daily for 4 days, followed by 3 days off. Monitor patients closely for adverse reactions. Risk D: Consider therapy modification

Cariprazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylcariprazine (DDCAR), the primary active metabolite of cariprazine, may increase. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cariprazine. Risk C: Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Decrease the dose of cilostazol to 50 mg twice daily when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Citalopram: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Citalopram. Risk C: Monitor therapy

Clindamycin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Clindamycin (Systemic). Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid this combination when possible. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose from 60 mg to 20 mg daily. Avoid concomitant use in patients already receiving reduced cobimetinib doses. Risk D: Consider therapy modification

Codeine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Avoidance, dose reduction, or increased monitoring for colchicine toxicity may be needed and will depend on brand, indication for colchicine use, renal/hepatic function, and use of a P-gp inhibitor. See full monograph for details. Risk D: Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Conivaptan. Risk C: Monitor therapy

Copanlisib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Copanlisib. Risk C: Monitor therapy

CycloSPORINE (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Crizotinib. Risk C: Monitor therapy

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

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Crizotinib. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors whenever possible. If combined use cannot be avoided, crizotinib dose reductions are required, which vary according to indication. See full interaction monograph for details. Risk D: Consider therapy modification

Dabrafenib: May enhance the QTc-prolonging effect of Crizotinib. Dabrafenib may decrease the serum concentration of Crizotinib. Crizotinib may increase the serum concentration of Dabrafenib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Additionally, monitor for decreased crizotinib efficacy and increased dabrafenib adverse effects. Risk C: Monitor therapy

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

Daridorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Daridorexant. Management: Limit the daridorexant dose to 25 mg, no more than once per night, when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Darifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Darifenacin. Risk C: Monitor therapy

Deflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Risk D: Consider therapy modification

DexAMETHasone (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapy

DiazePAM: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DiazePAM. Risk C: Monitor therapy

Dienogest: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dienogest. Risk C: Monitor therapy

DilTIAZem: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DilTIAZem. Risk C: Monitor therapy

DOCEtaxel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOCEtaxel. Risk C: Monitor therapy

Domperidone: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Domperidone. Risk X: Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

DroNABinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DroNABinol. Risk C: Monitor therapy

Dronedarone: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dronedarone. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dronedarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Ebastine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ebastine. Risk C: Monitor therapy

Elacestrant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elacestrant. Risk X: Avoid combination

Elbasvir and Grazoprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elbasvir and Grazoprevir. Risk C: Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Management: When combined with moderate CYP3A4 inhibitors, elexacaftor/tezacaftor/ivacaftor should be given in the morning, every other day. Ivacaftor alone should be given in the morning, every other day on alternate days. Risk D: Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with moderate CYP3A4 inhibitors. Avoid use of moderate CYP3A4 inhibitors in CYP2D6 IMs or PMs. Use in CYP2D6 EMs or IMs also taking strong or moderate CYP2D6 inhibitors is contraindicated. Risk D: Consider therapy modification

Encorafenib: Crizotinib may enhance the QTc-prolonging effect of Encorafenib. Crizotinib may increase the serum concentration of Encorafenib. Encorafenib may decrease the serum concentration of Crizotinib. Risk X: Avoid combination

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib. Risk X: Avoid combination

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: If coadministered with moderate CYP3A4 inhibitors, the max dose of eplerenone is 25 mg daily if used for heart failure; if used for hypertension initiate eplerenone 25 mg daily, titrate to max 25 mg twice daily. Risk D: Consider therapy modification

Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates). Risk C: Monitor therapy

Erlotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Erlotinib. Risk C: Monitor therapy

Escitalopram: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Risk C: Monitor therapy

Eszopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eszopiclone. Risk C: Monitor therapy

Etrasimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Etravirine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Etravirine. Risk C: Monitor therapy

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Risk C: Monitor therapy

Fedratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fedratinib. Risk C: Monitor therapy

Felodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Felodipine. Risk C: Monitor therapy

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Consider fentanyl dose reductions when combined with a moderate CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modification

Fexinidazole: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fexinidazole. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may decrease serum concentrations of the active metabolite(s) of Fexinidazole. Management: Consider alternatives to this combination. If combined, monitor for QT interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QT prolongation may be at even higher risk. Also monitor for reduced fexinidazole efficacy. Risk D: Consider therapy modification

Finerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Finerenone. Risk C: Monitor therapy

Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Management: Use of flibanserin with moderate CYP3A4 inhibitors is contraindicated. If starting flibanserin, start 2 weeks after the last dose of the CYP3A4 inhibitor. If starting a CYP3A4 inhibitor, start 2 days after the last dose of flibanserin. Risk X: Avoid combination

Fluorouracil Products: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Fluticasone (Nasal): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Nasal). Risk C: Monitor therapy

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Oral Inhalation). Risk C: Monitor therapy

Fosamprenavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosamprenavir. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant. Risk X: Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gepirone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Gepirone. Management: Reduce the gepirone dose by 50% if combined with moderate CYP3A4 inhibitors. Monitor for QTc interval prolongation with combined use. Risk D: Consider therapy modification

Glasdegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Glasdegib. Risk C: Monitor therapy

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

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the extended-release guanfacine dose 50% when combined with a moderate CYP3A4 inhibitor. Monitor for increased guanfacine toxicities when these agents are combined. Risk D: Consider therapy modification

Haloperidol: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

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

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Risk D: Consider therapy modification

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

Iloperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Iloperidone. Risk C: Monitor therapy

Infigratinib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Infigratinib. Risk X: Avoid combination

Irinotecan Products: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, the serum concentration of SN-38 may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Irinotecan Products. Risk C: Monitor therapy

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Moderate) may increase isavuconazole serum concentrations. Risk C: Monitor therapy

Isradipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Isradipine. Risk C: Monitor therapy

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

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions may be required; consult full drug interaction monograph content for age- and weight-specific dosage recommendations. Risk D: Consider therapy modification

Ivosidenib: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy

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

Lapatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lapatinib. Risk C: Monitor therapy

Larotrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy

Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination

Lemborexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lemborexant. Risk X: Avoid combination

Leniolisib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Leniolisib. Risk C: Monitor therapy

Lercanidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lercanidipine. Risk C: Monitor therapy

Levamlodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levamlodipine. Risk C: Monitor therapy

Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination

Levomethadone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levomethadone. Risk C: Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levomilnacipran. Risk C: Monitor therapy

Lidocaine (Systemic): CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Lidocaine (Systemic). Specifically, concentrations of monoethylglycinexylidide (MEGX) may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

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

Lonafarnib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lonafarnib. Risk X: Avoid combination

Lovastatin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lovastatin. Risk C: Monitor therapy

Lumateperone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lumateperone. Management: Limit the lumateperone dose to 21 mg once daily when used with a moderate CYP3A4 inhibitor. Risk D: Consider therapy modification

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: US labeling recommends reducing lurasidone dose by 50% with a moderate CYP3A4 inhibitor and initiating 20 mg/day, max 80 mg/day. Some non-US labels recommend initiating lurasidone 20 mg/day, max 40 mg/day. Avoid concurrent use of grapefruit products. Risk D: Consider therapy modification

Lurbinectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurbinectedin. Management: Avoid concomitant use of lurbinectedin and moderate CYP3A4 inhibitors when possible. If combined, consider a lurbinectedin dose reduction as clinically indicated. Risk D: Consider therapy modification

Macitentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Macitentan. Risk C: Monitor therapy

Manidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine. Risk C: Monitor therapy

Maraviroc: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Maraviroc. Risk C: Monitor therapy

Mavacamten: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a moderate CYP3A4 inhibitor. For those stable on mavacamten who are initiating a moderate CYP3A4 inhibitor, reduce mavacamten dose by one dose level. Risk D: Consider therapy modification

Meperidine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Meperidine. Risk C: Monitor therapy

Methadone: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for increased methadone toxicities (eg, respiratory depression, QTc interval prolongation). Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

MethylPREDNISolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapy

Methysergide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Methysergide. Risk X: Avoid combination

Midazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Midazolam. Management: Avoid concomitant use of nasal midazolam and moderate CYP3A4 inhibitors. Consider alternatives to use with oral midazolam whenever possible and consider using lower midazolam doses. Monitor patients for sedation and respiratory depression if combined. Risk D: Consider therapy modification

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

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

Mitapivat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mitapivat. Management: When coadministered with moderate CYP3A4 inhibitors, doses of mitapivat should not exceed 20 mg twice daily. Additionally, patients should be monitored for changes in hemoglobin response and increased mitapivat adverse effects. Risk D: Consider therapy modification

Mobocertinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Mobocertinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase serum concentrations of the active metabolite(s) of Mobocertinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Mobocertinib. Management: Avoid use of QT prolonging moderate CYP3A4 inhibitors with mobocertinib when possible. If combined, the mobocertinib dose should be reduced by approximately 50% (ie, from 160 mg to 80 mg, 120 mg to 40 mg, or 80 mg to 40 mg). Monitor QTc interval closely. Risk D: Consider therapy modification

Naldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine. Risk C: Monitor therapy

Nalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine. Risk C: Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Management: The use of naloxegol and moderate CYP3A4 inhibitors should be avoided. If concurrent use is unavoidable, reduce naloxegol dose to 12.5 mg once daily and monitor for signs of opiate withdrawal (eg, hyperhidrosis, chills, diarrhea, anxiety, irritability). Risk D: Consider therapy modification

Neratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib. Risk C: Monitor therapy

NIFEdipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NIFEdipine. Risk C: Monitor therapy

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

Nirogacestat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nirogacestat. Risk X: Avoid combination

Nisoldipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nisoldipine. Risk X: Avoid combination

Nitrendipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nitrendipine. Risk C: Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib tablets should be reduced to 150 mg twice daily and the dose of olaparib capsules should be reduced to 200 mg twice daily. Risk D: Consider therapy modification

Oliceridine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Oliceridine. Risk C: Monitor therapy

Olmutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy

Omaveloxolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Omaveloxolone. Management: Avoid this combination if possible. If coadministration is required, decrease the omaveloxolone dose to 100 mg daily and monitor closely for adverse reactions. If adverse reactions occur, decrease omaveloxolone to 50 mg daily. Risk D: Consider therapy modification

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Orelabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Orelabrutinib. Risk X: Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Risk C: Monitor therapy

Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

PACLitaxel (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Pacritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pacritinib. Risk X: Avoid combination

Palbociclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palbociclib. Risk C: Monitor therapy

Palovarotene: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palovarotene. Management: Avoid concomitant use of palovarotene and moderate CYP3A4 inhibitors when possible. If combined, decrease palovarotene dose by 50% as described in the full interaction monograph. Monitor for palovarotene toxicities when combined. Risk D: Consider therapy modification

Panobinostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Panobinostat. Risk C: Monitor therapy

PAZOPanib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of PAZOPanib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of PAZOPanib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Pemigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pemigatinib. Management: If combined use cannot be avoided, reduce the pemigatinib dose from 13.5 mg daily to 9 mg daily, or from 9 mg daily to 4.5 mg daily. Resume prior pemigatinib dose after stopping the moderate inhibitor once 3 half-lives of the inhibitor has passed. Risk D: Consider therapy modification

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Pexidartinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pexidartinib. Management: If combined use cannot be avoided, pexidartinib dose should be reduced. For the 125 mg capsules: reduce pexidartinib doses of 500 mg or 375 mg daily to 125 mg twice daily. Reduce pexidartinib 250 mg daily to 125 mg once daily. Risk D: Consider therapy modification

Pimavanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimavanserin. Risk C: Monitor therapy

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

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination

Pirtobrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pirtobrutinib. Risk C: Monitor therapy

PONATinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PONATinib. Risk C: Monitor therapy

Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification

Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination

Pralsetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider therapy modification

Prazepam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Prazepam. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Praziquantel. Risk C: Monitor therapy

QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Risk C: Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Crizotinib. Crizotinib may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Crizotinib may increase the serum concentration of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Moderate Risk). Risk C: Monitor therapy

QT-prolonging Miscellaneous Agents (Highest Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Crizotinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Crizotinib. QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors whenever possible. If combined use cannot be avoided, crizotinib dose reductions are required, which vary according to indication. See full interaction monograph for details. Risk D: Consider therapy modification

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Crizotinib may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, crizotinib dose adjustments are required, which vary according to indication. See full interaction monograph for details. Risk D: Consider therapy modification

QUEtiapine: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QUEtiapine. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QUEtiapine. Management: Monitor for increased quetiapine toxicities including QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Quinidine (Non-Therapeutic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Quinidine (Non-Therapeutic). Risk C: Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors. Monitor for increased ranolazine effects and toxicities during concomitant use. Risk D: Consider therapy modification

Red Yeast Rice: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Red Yeast Rice. Risk C: Monitor therapy

Regorafenib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Regorafenib. Risk C: Monitor therapy

Repotrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Repotrectinib. Risk X: Avoid combination

Rifabutin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rifabutin. Risk C: Monitor therapy

Rimegepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rimegepant. Management: If taking rimegepant for the acute treatment of migraine, avoid a second dose of rimegepant within 48 hours when used concomitantly with moderate CYP3A4 inhibitors. No dose adjustment needed if using rimegepant for prevention of episodic migraine. Risk D: Consider therapy modification

RisperiDONE: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Rivaroxaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rivaroxaban. This warning is more specifically for drugs that are inhibitors of both CYP3A4 and P-glycoprotein. For erythromycin, refer to more specific erythromycin-rivaroxaban monograph recommendations. Risk C: Monitor therapy

Roflumilast-Containing Products: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Roflumilast-Containing Products. Risk C: Monitor therapy

Rupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine. Risk C: Monitor therapy

Ruxolitinib (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib (Systemic). Risk C: Monitor therapy

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

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

Selpercatinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Selpercatinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Selpercatinib. Management: Avoid combination if possible. If use is necessary, reduce selpercatinib dose as follows: from 120mg twice/day to 80mg twice/day, or from 160mg twice/day to 120mg twice/day. Monitor QT interval more closely for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modification

Selumetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Selumetinib. Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modification

Sertindole: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Sertindole. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Sertindole. Risk X: Avoid combination

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

Silodosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin. Risk C: Monitor therapy

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

Simvastatin: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification

Sirolimus (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus (Conventional). Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Risk D: Consider therapy modification

Sirolimus (Protein Bound): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m² when used concomitantly with a moderate CYP3A4 inhibitor. Risk D: Consider therapy modification

Solifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Solifenacin. Risk C: Monitor therapy

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). Risk D: Consider therapy modification

Sparsentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sparsentan. Risk C: Monitor therapy

SUFentanil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SUFentanil. Risk C: Monitor therapy

SUNItinib: QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of SUNItinib. QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of SUNItinib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy. Risk D: Consider therapy modification

Tacrolimus (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Tacrolimus (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tacrolimus (Topical). Risk C: Monitor therapy

Tadalafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tadalafil. Risk C: Monitor therapy

Tamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy

Tazemetostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tazemetostat. Management: Avoid when possible. If combined, reduce tazemetostat dose from 800 mg twice daily to 400 mg twice daily, from 600 mg twice daily to 400 mg in AM and 200 mg in PM, or from 400 mg twice daily to 200 mg twice daily. Risk D: Consider therapy modification

Temsirolimus: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be increased. Risk C: Monitor therapy

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

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

Tezacaftor and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor and Ivacaftor. Management: If combined with moderate CYP3A4 inhibitors, give tezacaftor/ivacaftor in the morning, every other day; give ivacaftor in the morning, every other day on alternate days. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph Risk D: Consider therapy modification

Thiotepa: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Thiotepa. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Risk C: Monitor therapy

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

Tofacitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tofacitinib. Risk C: Monitor therapy

Tolterodine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolterodine. Risk C: Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Avoid this combination with Samsca brand of tolvaptan. Reduce dose for Jynarque brand: 90 mg AM and 30 mg PM, reduce to 45 mg AM and 15 mg PM; 60 mg AM and 30 mg PM, reduce to 30 mg AM and 15 mg PM; 45 mg AM and 15 mg PM, reduce to 15 mg AM and PM. Risk D: Consider therapy modification

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Risk C: Monitor therapy

TraMADol: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

TraZODone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraZODone. Risk C: Monitor therapy

Triazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and avoid a second dose for 24 hours when used with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

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

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Risk C: Monitor therapy

Valbenazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Valbenazine. Risk C: Monitor therapy

Vamorolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vamorolone. Risk C: Monitor therapy

Vardenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vardenafil. Management: Limit Levitra (vardenafil) dose to a single 5 mg dose within a 24-hour period if combined with moderate CYP3A4 inhibitors. Avoid concomitant use of Staxyn (vardenafil) and moderate CYP3A4 inhibitors. Combined use is contraindicated outside of the US. Risk D: Consider therapy modification

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with moderate CYP3A4 inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Verapamil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Verapamil. Risk C: Monitor therapy

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

VinBLAStine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinBLAStine. Risk C: Monitor therapy

VinCRIStine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinCRIStine. Risk C: Monitor therapy

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinCRIStine (Liposomal). Risk C: Monitor therapy

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

Vinflunine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Vinflunine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vinflunine. Risk C: Monitor therapy

Voclosporin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Voclosporin. Management: Decrease the voclosporin dose to 15.8 mg in the morning and 7.9 mg in the evening when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modification

Vorapaxar: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vorapaxar. Risk C: Monitor therapy

Warfarin: Crizotinib may enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Zanubrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg twice daily during coadministration with a moderate CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Risk D: Consider therapy modification

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Risk C: Monitor therapy

Zuranolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuranolone. Risk C: Monitor therapy

Food Interactions

Grapefruit juice may increase serum crizotinib levels. Management: Avoid grapefruit and grapefruit juice.

Reproductive Considerations

Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during treatment and for at least 45 days after the last crizotinib dose; males with partners who could become pregnant should use condoms during treatment and for at least 90 days after the final crizotinib dose.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, crizotinib may cause fetal harm if administered during pregnancy.

Breastfeeding Considerations

It is not known if crizotinib is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends against breastfeeding during treatment and for 45 days after the final crizotinib dose.

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Monitoring Parameters

ALK or ROS1 positivity (in tumor specimen) for non–small cell lung cancer (NSCLC); CBC with differential monthly (inflammatory myofibroblastic tumor [IMT] or NSCLC) or weekly for the first month (anaplastic large cell lymphoma [ALCL]), then monthly, and as clinically appropriate (monitor more frequently if grades 3 or 4 abnormalities observed or with fever or infection), LFTs (including ALT, AST, and total bilirubin) 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); electrolytes (baseline and as clinically indicated). Evaluate pregnancy status prior to use (in patients who could become pregnant). Monitor pulmonary symptoms (for interstitial lung disease/pneumonitis). Monitor heart rate and BP regularly; monitor ECG and electrolytes in patients with heart failure, bradycardia, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QT interval. Monthly assessment of visual symptoms for all patients is recommended; refer to eye specialist for evaluation with new visual symptoms. In ALCL or IMT, perform baseline ophthalmologic examinations prior to initiating therapy; a follow-up exam, including retinal evaluation, is recommended within 1 month of therapy initiation, every 3 months thereafter, and as clinically warranted. 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. Monitor for GI toxicity and hydration status. Monitor adherence.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]). Consider home BP monitoring; assess cholesterol profile every 3 to 6 months (ESC [Lyon 2022]).

Mechanism of Action

Crizotinib is a tyrosine kinase receptor inhibitor which inhibits 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. Crizotinib shows antitumor activity in cell lines that express echinoderm microtubule-associated protein-like 4, or EML4-ALK gene. Inhibition of ALK, ROS1, and c-Met phosphorylation is concentration-dependent. Crizotinib induces apoptosis and inhibits proliferation and ALK-mediated signaling in ALCL-derived cell lines.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: V_ss: 1772 L.

Protein binding: 91%.

Metabolism: Hepatic, predominantly via CYP3A4/5 (oxidation and dealkylation).

Bioavailability: 43% (range: 32% to 66%); bioavailability is reduced 14% with a high-fat meal.

Half-life elimination: Terminal: 42 hours.

Time to peak: 4 to 6 hours.

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

Clearance: 100 L/hour (single 250 mg oral dose); 60 L/hour (steady state at 250 mg twice daily).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: In patients with severe renal impairment (CrCl <30 mL/minute) not requiring dialysis, following a single 250 mg oral dose, the mean AUC_∞ and mean C_max were increased 79% and 34%, respectively, compared to patients with normal renal function.

Hepatic function impairment: Compared to subjects with normal hepatic function, steady-state crizotinib AUC and C_max decreased by 9% in subjects with mild hepatic impairment following 250 mg twice daily dosing. AUC and C_max increased by 14% and 9%, respectively, in subjects with moderate hepatic impairment following 200 mg twice daily dosing compared to subjects with normal hepatic function receiving 250 mg twice daily. Mean crizotinib AUC decreased by 35% and C_max decreased by 27% in subjects with severe hepatic impairment following 250 mg once daily dosing compared to subjects with normal hepatic function receiving 250 mg twice daily.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Xalkori;
(AR) Argentina: Xalkori;
(AT) Austria: Xalkori;
(AU) Australia: Xalkori;
(BD) Bangladesh: Crizonix;
(BE) Belgium: Xalkori;
(BG) Bulgaria: Xalkori;
(BR) Brazil: Xalkori;
(CH) Switzerland: Xalkori;
(CL) Chile: Xalkori;
(CN) China: Sai ke rui;
(CO) Colombia: Xalkori;
(CZ) Czech Republic: Xalkori;
(DE) Germany: Xalkori;
(DO) Dominican Republic: Xalkori;
(EC) Ecuador: Xalkori;
(EE) Estonia: Xalkori;
(EG) Egypt: Xalkori;
(ES) Spain: Xalkori;
(FI) Finland: Xalkori;
(FR) France: Xalkori;
(GB) United Kingdom: Xalkori;
(GR) Greece: Xalkori;
(HK) Hong Kong: Xalkori;
(HR) Croatia: Xalkori;
(HU) Hungary: Xalkori;
(ID) Indonesia: Xalkori;
(IE) Ireland: Xalkori;
(IN) India: Crizalk;
(IT) Italy: Xalkori;
(JO) Jordan: Xalkori;
(JP) Japan: Xalkori;
(KE) Kenya: Algrofin;
(KR) Korea, Republic of: Xalkori;
(KW) Kuwait: Xalkori;
(LB) Lebanon: Xalkori;
(LT) Lithuania: Xalkori;
(LV) Latvia: Xalkori;
(MX) Mexico: Xalkori;
(MY) Malaysia: Xalkori;
(NL) Netherlands: Xalkori;
(NO) Norway: Xalkori;
(NZ) New Zealand: Xalkori;
(PE) Peru: Xalkori;
(PH) Philippines: Xalkori;
(PL) Poland: Xalkori;
(PR) Puerto Rico: Xalkori;
(PT) Portugal: Xalkori;
(QA) Qatar: Xalkori;
(RO) Romania: Xalkori;
(RU) Russian Federation: Xalkori;
(SA) Saudi Arabia: Xalkori;
(SE) Sweden: Xalkori;
(SG) Singapore: Xalkori;
(SI) Slovenia: Xalkori;
(SK) Slovakia: Xalkori;
(TH) Thailand: Xalkori;
(TN) Tunisia: Xalkori;
(TR) Turkey: Xalkori;
(TW) Taiwan: Xalkori;
(UA) Ukraine: Xalkori;
(ZA) South Africa: Xalkori

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Topic 16810 Version 355.0

خرید پکیج

Crizotinib: Drug information