Note: Crizotinib is associated with a moderate or high emetic potential (ASCO [Hesketh 2020]); antiemetics are recommended to prevent nausea and vomiting.
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.
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 |
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 as soon as remembered unless it is <6 hours prior to the next scheduled dose (skip the dose if <6 hours before the next dose). 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.
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.
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.
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.
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 treatment 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.
(For additional information see "Crizotinib: Pediatric drug information")
Note: Crizotinib is associated with a moderate emetic potential (Hesketh 2017); antiemetics should be offered.
Anaplastic large cell lymphoma (ALCL); systemic anaplastic lymphoma kinase [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 with BSA ≥0.6 m2:
0.6 to 0.8 m2: Oral: 200 mg twice daily.
0.81 to 1.16 m2: Oral: 250 mg twice daily.
1.17 to 1.51 m2: Oral: 400 mg twice daily.
1.52 to 1.69 m2: Oral: 450 mg twice daily.
≥1.70 m2: Oral: 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): Children and Adolescents: Oral:
Body surface area |
First dose reduction |
Second dose reductiona |
---|---|---|
aPermanently discontinue crizotinib if unable to tolerate crizotinib after 2 dose reductions. | ||
0.6 to 0.8 m2 |
250 mg once daily |
Permanently discontinue crizotinib |
≥0.81 to 1.16 m2 |
200 mg twice daily |
250 mg once daily |
≥1.17 to 1.69 m2 |
250 mg twice daily |
200 mg twice daily |
≥1.70 m2 |
400 mg twice daily |
250 mg twice daily |
Adverse reaction |
Crizotinib dose adjustment |
---|---|
ANC <500/mm3 |
1st occurrence: Withhold crizotinib until recovery to ANC >1,000/mm3, then resume at the next lower dose. |
2nd occurrence: For uncomplicated grade 4 neutropenia, either withhold crizotinib until recovery to ANC >1,000/mm3 then 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. |
Life-threatening anemia; urgent intervention indicated |
Withhold crizotinib until recovery to ≥8 g/dL, then resume at the next lower dose. Permanently discontinue for recurrence. |
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. |
Symptomatic bradycardia, may be severe and medically significant with medical intervention indicated |
Withhold until recovery to the following age-dependent heart rate (based on 2.5th 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 |
Life-threatening bradycardia 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 2nd 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. |
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. |
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. |
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. |
Anaplastic large cell lymphoma (ALCL); systemic anaplastic lymphoma kinase (ALK)-positive, relapsed or refractory: Note: Kidney function is estimated using the Schwartz equation in pediatric patients.
Children and Adolescents: Oral:
CrCl ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.
CrCl <30 mL/minute/1.73 m2 not requiring dialysis: Reduce dosage according to the following BSA recommendations.
BSA 0.6 to 0.8 m2: Do not initiate or permanently discontinue (if existing therapy).
BSA ≥0.81 to 1.16 m2: 250 mg once daily.
BSA ≥1.17 to 1.69 m2: 200 mg twice daily.
BSA ≥1.7 m2: 250 mg twice daily.
Anaplastic large cell lymphoma (ALCL); systemic anaplastic lymphoma kinase (ALK)-positive, relapsed or refractory: Children and Adolescents: Oral:
Baseline hepatic impairment:
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): Reduce dosage according to the following BSA recommendations.
BSA 0.6 to 0.8 m2: 250 mg once daily.
BSA ≥0.81 to 1.16 m2: 200 mg twice daily.
BSA ≥1.17 to 1.69 m2: 250 mg twice daily.
BSA ≥1.7 m2: 400 mg twice daily.
Severe impairment (total bilirubin >3 times ULN and any AST):
BSA 0.6 to 0.8 m2: Do not administer crizotinib.
BSA ≥0.81 to 1.16 m2: 250 mg once daily.
BSA ≥1.17 to 1.69 m2: 200 mg twice daily.
BSA ≥1.7 m2: 250 mg twice daily.
Hepatotoxicity during treatment:
ALT or AST >5 x ULN with total bilirubin ≤1.5 x ULN: Withhold treatment until recovery to baseline or ≤3 x ULN, then resume at the next lower dose. Refer to "Dosage Adjustment for Toxicity" for dosage reduction levels table.
ALT or AST >3 x ULN with concurrent total bilirubin elevation >1.5 x ULN in the absence of cholestasis or hemolysis: Permanently discontinue crizotinib.
Refer to adult dosing.
Anaplastic large cell lymphoma, systemic ALK-positive, relapsed or refractory:
BSA |
First dose reduction |
Second dose reductiona |
---|---|---|
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 |
Adverse reaction severity |
Crizotinib dose modification |
---|---|
Hematologic toxicities | |
ANC <500/mm3 |
1st occurrence: Withhold crizotinib until recovery to ANC >1,000/mm3, then resume at the next lower dose. |
2nd occurrence: For uncomplicated grade 4 neutropenia, either withhold crizotinib until recovery to ANC >1,000/mm3 then 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 2nd 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. |
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 therapy.
Adverse reaction severity |
Crizotinib dose modification |
---|---|
aExcept lymphopenia (unless associated with clinical events [eg, opportunistic infections]). | |
Hematologic toxicitya | |
Grade 3 hematologic toxicitya |
Withhold crizotinib until recovery to grade ≤2, then resume at the same dose. |
Grade 4 hematologic toxicitya |
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 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. |
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Xalkori: 200 mg, 250 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Xalkori: 200 mg, 250 mg
Available through specialty pharmacies. Further information may be obtained from the manufacturer, Pfizer, at 1-877-744-5675, or at http://www.pfizerpro.com
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202570s030lbl.pdf#page=35, must be dispensed with this medication.
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.
Note: Crizotinib is associated with a moderate emetic potential (Hesketh 2017); antiemetics should be offered.
Oral: Administer with or without food. Swallow capsules whole (do not crush, dissolve, or open capsules). If vomiting occurs after dose, administer the next dose at the regularly scheduled time.
Patients unable to swallow capsules whole: Per the manufacturer, the following methodology may be utilized. Note: This method has not been formally evaluated in pharmacokinetic studies (manufacturer data on file).
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.
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 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).
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.
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).
Crizotinib may be confused with afatinib, alectinib, brigatinib, cabozantinib, capmatinib, ceritinib, cobimetinib, copanlisib, crizanlizumab, erlotinib, gefitinib, lorlatinib, PONATinib
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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%), dysgeusia (26%), dyspepsia (8% to 14%), nausea (55% to 56%), vomiting (46% to 47%)
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, dysesthesia, hypoesthesia, myasthenia, neuralgia, paresthesia)
Neuromuscular & skeletal: Limb pain (16%)
Ophthalmic: Visual disturbance (60% to 71%; onset: <1 week; including blurred vision, decreased visual acuity, diplopia, photophobia, photopsia, visual field defect, visual impairment, 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%)
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 (3% to 4%; includes acute respiratory distress syndrome, pneumonitis)
<1%:
Hepatic: Hepatotoxicity
Ophthalmic: Vision loss
Frequency not defined:
Cardiovascular: Cardiac arrhythmia, septic shock
Dermatologic: Burning sensation of skin
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
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
Concerns related to adverse effects:
• Cardiovascular toxicity: Symptomatic bradycardia may occur; heart rate <50 beats/minute has occurred. If possible, avoid concurrent use with other agents known to cause bradycardia (eg, beta blockers, nondihydropyridine calcium channel blockers, clonidine, digoxin). If symptomatic bradycardia (not life-threatening) occurs, withhold treatment until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute, evaluate concurrent medications, and potentially reduce crizotinib dose. Permanently discontinue for life-threatening bradycardia due to crizotinib; if life-threatening bradycardia occurs and concurrent medications associated with bradycardia can be discontinued or dose adjusted, restart crizotinib at a reduced dose (with frequent monitoring). QTc prolongation has been observed; may require treatment interruption, dosage reduction, or discontinuation. 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. GI toxicity may require therapy interruption and dose reduction in patients with anaplastic large cell lymphoma; consider supportive care, such as, antiemetics, antidiarrheals, 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. Hepatotoxicity may require treatment interruption, dose reduction, and/or permanent discontinuation.
• Ocular toxicities: Visual disorders commonly occur with crizotinib. The most common visual symptoms were blurred vision and visual impairment. Grade 3 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. For new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes), obtain ophthalmic evaluation (including best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography, and other evaluations as appropriate). In the management of anaplastic large cell lymphoma, withhold crizotinib for any grade 3 or 4 ocular disorder (pending evaluation); discontinue permanently for grade 3 or 4 ocular disorders if no other cause is identified. 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. Permanently discontinue if treatment-related ILD/pneumonitis is confirmed.
Disease-related concerns:
• Hepatic impairment: Reduce the initial dose in patients with preexisting moderate or severe hepatic impairment. Crizotinib levels are increased in patients with moderate and severe hepatic impairment.
• Renal impairment: Reduce the initial dose in patients with preexisting severe renal impairment not requiring dialysis.
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, 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.
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), OCT1, OCT2
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
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: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. See interaction monograph for details. Use extra caution in patients with impaired renal and/or hepatic function. 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: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dabrafenib. 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
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
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, two elexacaftor/tezacaftor/ivacaftor (100 mg/50 mg/75 mg) tablets should be given in the morning, every other day. Ivacaftor (150 mg) 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: 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 Encorafenib. Management: Avoid use of encorafenib and moderate CYP3A4 inhibitors when possible. If combined, decrease encorafenib dose from 450 mg to 225 mg; 300 mg to 150 mg; and 225 mg or 150 mg to 75 mg. Monitor closely for QT interval prolongation. Risk D: Consider therapy modification
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
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
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
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
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
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
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. Risk X: Avoid combination
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
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 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
MethylPREDNISolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of MethylPREDNISolone. Risk C: Monitor therapy
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
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
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
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
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
Palbociclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palbociclib. Risk C: Monitor therapy
Panobinostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Panobinostat. Risk C: Monitor therapy
PAZOPanib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PAZOPanib. 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: Avoid use of pexidartinib with moderate CYP3A4 inhibitors if possible. If combined, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg per day to 200 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
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
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 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 (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
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
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: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Roflumilast. 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
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
SUNItinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SUNItinib. 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
Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. 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
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
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
Grapefruit juice may increase serum crizotinib levels. Management: Avoid grapefruit and grapefruit juice.
Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use adequate contraception during treatment and for at least 45 days after the last crizotinib dose; males with female partners of reproductive potential should use condoms during treatment and for at least 90 days after the final crizotinib dose.
Based on the mechanism of action and data from animal reproduction studies, crizotinib may cause fetal harm if administered during pregnancy.
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 dose.
Avoid grapefruit and grapefruit juice.
ALK or ROS1 positivity (in tumor specimen) for non-small cell lung cancer (NSCLC); CBC with differential monthly (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 every 2 weeks for the first 2 months, then monthly and as clinically appropriate (monitor more frequently if grades 2, 3, or 4 abnormalities observed); renal function (baseline and periodic). Monitor pulmonary symptoms (for interstitial lung disease/pneumonitis). Monitor heart rate and BP; monitoring ECG and electrolytes in patients with heart failure, bradycardia, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QT interval. In ALCL, 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.
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.
Distribution: Vss: 1772 L
Protein binding: 91%
Metabolism: Hepatic, 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)
Renal function impairment: In a limited number of patients with severe renal impairment (not requiring dialysis), for a single 250 mg oral dose, the mean AUC∞ and mean Cmax were increased 79% and 34%, respectively, compared to patients with normal renal function.
Hepatic function impairment: Compared to subjects with normal hepatic function, steady-state crizotinib AUC and Cmax decreased by 9% in subjects with mild hepatic impairment following 250 mg twice daily dosing. AUC and Cmax 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 Cmax 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.
Capsules (Xalkori Oral)
200 mg (per each): $392.18
250 mg (per each): $392.18
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