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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK) and ROS1 (c-ros)
    Used in patients with metastatic non-small cell lung cancer (NSCLC) that is ALK-positive or ROS1-positive
    Significant response rates noted in clinical trials; dosage adjustments and/or treatment discontinuation may be necessary due to adverse events

    COMMON BRAND NAMES

    XALKORI

    HOW SUPPLIED

    XALKORI Oral Cap: 200mg, 250mg

    DOSAGE & INDICATIONS

    For the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)- or ROS1- positive as detected by an FDA-approved test.
    Oral dosage
    Adults

    250 mg orally twice daily. Continue until disease progression or unacceptable toxicity. Treatment with crizotinib monotherapy (n = 173) significantly improved the primary outcome of progression-free survival (PFS) compared with chemotherapy (pemetrexed, n = 99; docetaxel, n = 72) in a randomized, open label trial of patients with ALK-positive metastatic NSCLC previously treated with platinum based therapy (7.7 vs. 3 months); additionally, the objective response rate (ORR) was 65% vs. 20% and duration of response was 7.4 months vs. 5.6 months. Overall survival was not improved (20.3 months vs. 22.8 months) at an interim analysis; however, 64% of patients randomized to chemotherapy had crossed over to receive crizotinib after disease progression. Crizotinib (n = 171) also significantly improved PFS compared with chemotherapy (pemetrexed/cisplatin, n = 91; pemetrexed/carboplatin, n = 78) in a separate multicenter, randomized, open-label, phase 3 study of previously untreated patients with ALK-positive locally advanced, recurrent, or metastatic non-squamous NSCLC (10.9 vs. 7 months); ORR was also significantly improved (74% vs. 45%), and the median duration of response was 11.3 months vs. 5.3 months, respectively. Overall survival, possibly confounded by a crossover rate of 70% from chemotherapy to crizotinib, was not significantly improved. Finally, treatment with crizotinib resulted in an ORR of 66% for a median duration of 18.3 months by independent radiology review (IRR; n = 50) in a multicenter, single-arm clinical trial in patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC); most responses were partial responses.

    MAXIMUM DOSAGE

    Adults

    500 mg/day PO.

    Geriatric

    500 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Crizotinib has not been studied in patients with hepatic impairment; however, crizotinib is extensively metabolized. Hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies excluded patients with AST or ALT greater than 2.5 x upper limit of normal (ULN) or with enzymes greater than 5 x ULN if due to liver metastases. Patients with total bilirubin greater than 1.5 x ULN were also excluded. The manufacturer recommends that crizotinib should be used with caution in patients with hepatic impairment.
     
    Treatment-Related Hepatotoxicity:
    ALT or AST more than 5 times ULN with total bilirubin less than or equal to 1.5 times ULN: Hold crizotinib. When ALT/AST recover to less than or equal to 3 times ULN or baseline, resume treatment at the next lower dose. Permanently discontinue treatment if unable to tolerate crizotinib 250 mg PO once daily.
    ALT or AST more than 3 times ULN with total bilirubin more than 1.5 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue treatment.

    Renal Impairment

    CrCl greater than or equal to 30 mL/min: No starting dose adjustment for crizotinib is needed.
    CrCl less than 30 mL/min, not requiring dialysis: 250 mg PO once daily. There are no data for patients with end-stage renal disease.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be taken orally with or without food.
    Have the patient swallow capsule whole. Do not crush or chew.
    If a dose is missed, it can be taken up to 6 hours before the next dose is due to maintain the twice daily regimen. Do not take both doses at the same time.
    If vomiting occurs after taking a dose, do not repeat the dose. Take the next dose at the regular time.

    STORAGE

    XALKORI :
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Confirmation of ALK-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test is required for the use of crizotinib.

    Pneumonitis

    Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and other causes should be excluded. Crizotinib should be permanently discontinued in patients with treatment-related interstitial lung disease or pneumonitis. Crizotinib has been associated with severe, life-threatening, or fatal treatment-related interstitial lung disease or pneumonitis in clinical trials. Most cases occurred within 3 months of treatment initiation.

    Hepatic disease

    Use crizotinib with caution in patients with severe hepatic disease; fatal drug-induced hepatotoxicity has been reported with crizotinib use. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor LFTs and bilirubin levels before treatment initiation, every 2 weeks for the first 2 months of treatment, then monthly and as clinically indicated thereafter. More frequent testing is needed in patients who develop increased transaminases. Laboratory alterations should be managed with dose reduction, treatment interruption, or discontinuation.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, geriatric, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    QT prolongation has been reported with the use of crizotinib; therefore, crizotinib should be avoided in patients with congenital long QT syndrome. Periodic ECG and electrolyte monitoring is recommended in patients with congestive heart failure, bradyarrhythmias (bradycardia), electrolyte imbalance (especially hypokalemia or hypomagnesemia), or in patients who are taking concomitant medications known to prolong the QT interval. Use crizotinib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Bradycardia (heart rate < 50 beats per minute) was also reported in clinical trials. If possible, do not use crizotinib in combination with other agents known to cause bradycardia (i.e., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin). Monitor heart rate and blood pressure regularly. Crizotinib treatment interruption, dosage adjustment, or treatment discontinuation may be necessary in patients who develop QT prolongation or bradycardia.

    Children, infants, neonates

    The safety and efficacy of crizotinib in neonates, infants, children, and adolescents have not been established. Decreased bone formation in growing long bones was observed in animal studies with dosing that exceeded the human adult dose by approximately 10 times the normal dose. Other toxicities have not been evaluated.

    Renal failure, renal impairment

    No starting dose adjustment for crizotinib is needed for patients with mild (CrCl 60—90 ml/min) to moderate (Cr 30—60 ml/min) renal impairment as steady-state concentrations in these patients are similar to patients with normal renal function (CrCl > 90 ml/min). The manufacturer states that the potential need for starting dose adjustments in patients with severe renal impairment (CrCl < 30 ml/min) cannot be determined as data are available for only 1 patient in trials. There are no data for patients with end-stage renal disease (renal failure). The manufacturer recommends caution be used when administering crizotinib to patients with severe renal impairment or end-stage renal disease.

    Driving or operating machinery, optic neuritis, visual disturbance

    Serious vision disorders and visual disturbance were reported in patients during crizotinib clinical trials; optic nerve disorder (optic neuritis) and optic atrophy have been reported as potential causes of vision loss. These events generally started within 2 weeks of the start of therapy. Ophthalmological evaluation, including best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations should be performed for any new onset of decreased vision. Discontinue crizotinib in patients with new onset of severe vision loss (best corrected vision less than 20/200 in one or both eyes); there is insufficient information regarding the resumption of crizotinib therapy in patients with a severe visual loss. Caution should be used when driving or operating machinery by patients who experience vision disorders.

    Pregnancy

    Crizotinib may cause fetal harm based on its mechanism of action and animal studies showing potential for maternal-fetal transmission; however, there are no well-controlled studies in pregnant women. In animal studies, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the maximum recommended doses. Women of childbearing potential should be advised to avoid becoming pregnant while receiving crizotinib and for at least 45 days after discontinuing therapy. When administered to pregnant rats during organogenesis, postimplantation loss was increased at approximately 0.6 times the recommended human dose based on AUC. No teratogenic effects were observed in rats or rabbits at doses up to 2.7 and 1.6 times the recommended human dose based on AUC, respectively; fetal body weights were reduced at both dose levels. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, the patient should be cautioned of the potential hazard to the fetus.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during crizotinib treatment. Crizotinib can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 45 days after treatment with crizotinib. Men with female partners of reproductive potential should use condoms during treatment with crizotinib and for at least 90 days after the last dose due to a potential for male-mediated teratogenicity. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving treatment should be apprised of the potential hazard to the fetus. In addition, based on animal data, crizotinib may cause infertility in females and males; it is not known whether these effects on fertility are reversible.

    Breast-feeding

    It is not known whether crizotinib is excreted into human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with crizotinib and for 45 days after the last dose.

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 5.7-17.0
    bradycardia / Rapid / 5.0-14.0
    neutropenia / Delayed / 11.0-12.0
    hypophosphatemia / Delayed / 5.0-10.0
    lymphopenia / Delayed / 7.0-9.0
    pulmonary embolism / Delayed / 2.9-6.0
    dyspnea / Early / 2.3-4.1
    hypokalemia / Delayed / 4.0-4.0
    QT prolongation / Rapid / 2.0-3.0
    fatigue / Early / 0-3.0
    syncope / Early / 0-2.4
    leukopenia / Delayed / 0-2.0
    constipation / Delayed / 2.0-2.0
    diarrhea / Early / 0-2.0
    esophagitis / Delayed / 0-2.0
    vomiting / Early / 1.0-2.0
    anorexia / Delayed / 0-2.0
    pneumonitis / Delayed / 0.5-1.6
    infection / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    dysphagia / Delayed / 1.0-1.0
    nausea / Early / 1.0-1.0
    stomatitis / Delayed / 0-1.0
    weight gain / Delayed / 1.0-1.0
    weight loss / Delayed / 1.0-1.0
    edema / Delayed / 0-1.0
    dizziness / Early / 1.0-1.0
    headache / Early / 0-1.0
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    optic atrophy / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    esophageal ulceration / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known

    Moderate

    peripheral neuropathy / Delayed / 19.0-21.0
    anemia / Delayed / 0-9.0
    thrombocytopenia / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    photopsia / Delayed / Incidence not known
    photophobia / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 26.0-26.0
    abdominal pain / Early / 26.0-26.0
    cough / Delayed / 0-23.0
    fever / Early / 0-19.0
    musculoskeletal pain / Early / 0-16.0
    dyspepsia / Early / 8.0-14.0
    asthenia / Delayed / 0-13.0
    rash (unspecified) / Early / 9.0-11.0
    pharyngitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    diplopia / Early / Incidence not known
    dysesthesia / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    weakness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with crizotinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acebutolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Acetaminophen; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with crizotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Acetaminophen; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with crizotinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of crizotinib, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Afatinib: (Major) Reduce the dose of afatinib by 10 mg if not tolerated when coadministration with crizotinib is necessary; monitor for afatinib-related adverse reactions. Resume the previous dose of afatinib as tolerated after discontinuation of crizotinib. Afatinib is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. Coadministration with another P-gp inhibitor given 1 hour before afatinib (single dose) increased the afatinib AUC 48%; there was no change in the afatinib AUC when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC of afatinib was 119% when coadministered with the same P-gp inhibitor, and was 111% when the P-gp inhibitor was administered 6 hours after afatinib.
    Albuterol: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with short-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with short-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If crizotinib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alfuzosin: (Major) Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with alfuzosin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Coadministration of alfuzosin and crizotinib may increase the risk for QT prolongation and increase exposure to alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Crizotinib has also been associated with concentration-dependent QT prolongation. Administration with another moderate CYP3A4 inhibitor increased the AUC and Cmax of alfuzosin by 1.3-fold and 1.5-fold, respectively.
    Aliskiren; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Alogliptin; Metformin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Alprazolam: (Moderate) Monitor for an increase in alprazolam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; consider reducing the dose of alprazolam as clinically appropriate. Crizotinib is a moderate CYP3A substrate and alprazolam is a CYP3A substrate. Drugs inhibiting this metabolic pathway may have a profound effect on the clearance of alprazolam. Coadministration with a strong CYP3A4 inhibitor increased plasma alprazolam concentrations by 3.98-fold.
    Amiodarone: (Major) Avoid coadministration of amiodarone with crizotinib due to the risk of additive QT prolongation and torsade de pointes (TdP); an increase in treatment-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) may also occur. If concomitant use is unavoidable, monitor ECGs and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation. Crizotinib is a CYP3A4 substrate and a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Amiodarone, a CYP3A4 substrate, moderate CYP3A4 inhibitor, and Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP, although the frequency of TdP is less than with other Class III agents.
    Amitriptyline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Telmisartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of crizotinib with clarithromycin due to increased crizotinib exposure; additive risks of QT prolongation are also possible. Crizotinib is a CYP3A substrate that is associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A inhibitor that has an established risk of QT prolongation and torsade de pointes (TdP). Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of crizotinib with clarithromycin due to increased crizotinib exposure; additive risks of QT prolongation are also possible. Crizotinib is a CYP3A substrate that is associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A inhibitor that has an established risk of QT prolongation and torsade de pointes (TdP). Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Anagrelide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Crizotinib has also been associated with QT prolongation.
    Apixaban: (Moderate) Use apixaban and crizotinib together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Crizotinib is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased with moderate inhibitors.
    Apomorphine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with apomorphine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of crizotinib, a moderate CYP3A4 inhibitor, and aprepitant/fosaprepitant, a CYP3A4 substrate, due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Increased crizotinib exposure may also occur with multi-day regimens of oral aprepitant, resulting in increased crizotinib-related adverse reactions, including QT prolongation. Crizotinib is a CYP3A4 substrate and aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Arformoterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with aripiprazole due to an increased risk of QT prolongation; also monitor for an increase in aripiprazole-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Aripiprazole is a CYP3A4 substrate; QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of crizotinib and a CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of crizotinib and a CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. When adjunctive Abilify is administered to patients with major depressive disorder, Abilify should be administered without dosage adjustment. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with crizotinib due to the risk of QT prolongation; discontinue crizotinib or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant use is unavoidable, frequently monitor electrocardiograms and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid coadministration of lumefantrine with crizotinib if possible due to the risk of QT prolongation; an increase in lumefantrine-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation. Additionally, crizotinib is a moderate CYP3A4 inhibitor and lumefantrine is a CYP3A4 substrate. The potential for increased lumefantrine concentrations when administered with CYP3A4 inhibitors could further increase the risk of QT prolongation. (Major) Because both drugs have been associated with QT prolongation, avoid coadministration of artemether with crizotinib if possible; an increase in artemether-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; a dose reduction, interruption of therapy, or discontinuation of therapy may be needed for crizotinib patients if QT prolongation occurs. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Artemether is a CYP3A4 substrate that is also associated with QT prolongation.
    Asenapine: (Major) Avoid coadministration of asenapine with crizotinib due to the risk of QT prolongation. Both crizotinib and asenapine have been associated with QT prolongation; the manufacturer of asenapine recommends avoiding concomitant use. If coadministration cannot be avoided, monitor ECGs and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with crizotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Atazanavir: (Major) Avoid coadministration of crizotinib with atazanavir due to the risk of increased crizotinib-related adverse reactions; increased atazanavir-related adverse reactions may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor; atazanavir is also a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of crizotinib with atazanavir due to the risk of increased crizotinib-related adverse reactions; increased atazanavir-related adverse reactions may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor; atazanavir is also a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated. (Major) Avoid coadministration of crizotinib with cobicistat due to increased crizotinib exposure; increased plasma concentrations of cobicistat may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is also a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Atenolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Atenolol; Chlorthalidone: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Atomoxetine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with atomoxetine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Prolongation of the QT interval has occurred during therapeutic use of atomoxetine as well as following overdose. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of crizotinib with phenobarbital due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Avanafil: (Major) The maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours if coadministration with crizotinib is necessary. Crizotinib is a moderate CYP3A substrate and avanafil is a CYP3A substrate. Coadministration with another moderate CYP3A4 inhibitor increased avanafil (single dose) exposure by 3-fold and prolonged the half-life of avanafil to approximately 8 hours in healthy volunteers.
    Azithromycin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with azithromycin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Reports of QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Bedaquiline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of bedaquiline with crizotinib is necessary; an increase in bedaquiline-related adverse reactions may also occur. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if the QTc interval is prolonged 500 msec or more or greater than 60 msec change from baseline. Both drugs have been associated with QT prolongation. Coadministration may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of crizotinib with phenobarbital due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%. (Moderate) Closely monitor for ergotamine-related adverse reactions, including vasospasm leading to cerebral ischemia and/or ischemia of the extremities, if coadministration with crizotinib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic index and crizotinib is a moderate CYP3A inhibitor. While ergot toxicity has not been reported with moderate CYP3A inhibition, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine.
    Bendroflumethiazide; Nadolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Beta-adrenergic blockers: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Betaxolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with metronidazole. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with metronidazole. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Bisoprolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Boceprevir: (Major) Avoid coadministration of crizotinib with boceprevir due to increased crizotinib exposure; an increase in boceprevir exposure may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Boceprevir is a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Bosentan: (Major) Monitor for an increase in bosentan-related adverse reactions if coadministration with crizotinib is necessary; this risk is increased if the patient is also receiving a CYP2C9 inhibitor. Treatment with bosentan and crizotinib with a CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A substrate and crizotinib is a moderate CYP3A4 inhibitor. Because bosentan is also metabolized by CYP2C9, a large increase in bosentan plasma concentrations may occur if the patient is receiving concomitant treatment with a CYP2C9 inhibitor in addition to crizotinib.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and crizotinib due to increased exposure to bosutinib. Bosutinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased bosutinib exposure by 2-fold.
    Brexpiprazole: (Moderate) Monitor for an increase in brexpiprazole-related adverse reactions if coadministration with crizotinib is necessary; this risk is higher if the patient is also receiving an inhibitor of CYP2D6, and requires a dose adjustment. Brexpiprazole is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Because brexpiprazole is also a CYP2D6 substrate, a 75% dose reduction is necessary if the patient is also receiving a CYP2D6 inhibitor in addition to crizotinib; the brexpiprazole dose may be returned to its original level when the CYP2D6 inhibitor is discontinued.
    Brimonidine; Timolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Bromocriptine: (Major) Do not exceed a maximum dose of bromocriptine (Cycloset) 1.6 mg once daily for the treatment of Type 2 diabetes if coadministration with crizotinib is necessary. The manufacturer of bromocriptine (Parlodel) recommends monitoring for bromocriptine-related adverse reactions if concomitant use with crizotinib is necessary. Bromocriptine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased bromocriptine exposure by 2.8-fold.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Budesonide: (Moderate) Avoid coadministration of systemic budesonide with crizotinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with crizotinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions and toxicities if coadministration with crizotinib is necessary. Lidocaine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Buprenorphine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of buprenorphine with crizotinib is necessary. Also monitor frequently for sedation and respiratory depression, especially if crizotinib is added after a stable dose of buprenorphine is achieved; a dose adjustment of buprenorphine may be necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Buprenorphine is a CYP3A4 substrate that has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Buprenorphine; Naloxone: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of buprenorphine with crizotinib is necessary. Also monitor frequently for sedation and respiratory depression, especially if crizotinib is added after a stable dose of buprenorphine is achieved; a dose adjustment of buprenorphine may be necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Buprenorphine is a CYP3A4 substrate that has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Bupropion: (Moderate) Monitor for an increase in bupropion-related adverse reactions if coadministration with crizotinib is necessary. Crizotinib is an inhibitor of CYP2B6 in vitro, and bupropion is extensively metabolized by CYP2B6 in vitro.
    Bupropion; Naltrexone: (Moderate) Monitor for an increase in bupropion-related adverse reactions if coadministration with crizotinib is necessary. Crizotinib is an inhibitor of CYP2B6 in vitro, and bupropion is extensively metabolized by CYP2B6 in vitro.
    Buspirone: (Major) A low dose of buspirone (e.g., 2.5 mg twice daily) is recommended if coadministration with crizotinib is necessary, with subsequent dose adjustments based on clinical assessment; monitor for buspirone-related adverse reactions, especially if crizotinib is added after a stable dose of buspirone is achieved. Buspirone is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of buspirone by 6-fold and was accompanied by increased buspirone-related adverse reactions.
    Caffeine; Ergotamine: (Moderate) Closely monitor for ergotamine-related adverse reactions, including vasospasm leading to cerebral ischemia and/or ischemia of the extremities, if coadministration with crizotinib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic index and crizotinib is a moderate CYP3A inhibitor. While ergot toxicity has not been reported with moderate CYP3A inhibition, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Crizotinib is a mild PGP inhibitor/substrate in vitro. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Crizotinib is a mild PGP inhibitor/substrate in vitro. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions. (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Carbamazepine: (Major) Avoid coadministration of crizotinib with carbamazepine due to decreased crizotinib exposure; increased carbamazepine exposure may also occur. Crizotinib is a CYP3A substrate and moderate CYP3A4 inhibitor and carbamazepine is a strong CYP3A inducer and CYP3A4 substrate. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Carteolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Carvedilol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Ceritinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of ceritinib with crizotinib is necessary, as both drugs have been associated with concentration-dependent QT prolongation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for both drugs if QT prolongation occurs.
    Chloramphenicol: (Major) Avoid coadministration of crizotinib with chloramphenicol due to increased crizotinib exposure. Crizotinib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Chloroquine: (Major) Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with other drugs known to prolong the QT interval, such as chloroquine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib. Crizotinib has been associated with concentration-dependent QT prolongation. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpheniramine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Chlorpromazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with chlorpromazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients for QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Crizotinib has also been associated with concentration-dependent QT prolongation.
    Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with crizotinib, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. Crizotinib is a moderate CYP3A4 inhibitor both in vitro and in vivo. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Ciprofloxacin: (Major) Monitor ECGs for QT prolongation, monitor electrolytes, and watch for an increase in crizotinib-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) if coadministration with ciprofloxacin is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ciprofloxacin is a moderate CYP3A4 inhibitor; rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsade de pointes (TdP), use of crizotinib with cisapride is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride; crizotinib is also associated with QT prolongation.
    Citalopram: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of crizotinib with citalopram is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs are associated with concentration-dependent QT prolongation.
    Clarithromycin: (Major) Avoid coadministration of crizotinib with clarithromycin due to increased crizotinib exposure; additive risks of QT prolongation are also possible. Crizotinib is a CYP3A substrate that is associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A inhibitor that has an established risk of QT prolongation and torsade de pointes (TdP). Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Clomipramine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clonazepam: (Moderate) Monitor for an increase in clonazepam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary. Crizotinib is a moderate CYP3A substrate and clonazepam is a CYP3A substrate. Although clinical studies have not been performed, based on the involvement of CYP3A in clonazepam metabolism, inhibitors of this enzyme system may increase clonazepam exposure and should be used cautiously.
    Clozapine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of clozapine with crizotinib is necessary. An increase in clozapine-related adverse reactions (e.g., life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis) may also occur; consider a dose reduction if necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Clozapine is a CYP3A4 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation.
    Cobicistat: (Major) Avoid coadministration of crizotinib with cobicistat due to increased crizotinib exposure; increased plasma concentrations of cobicistat may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is also a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of crizotinib with cobicistat due to increased crizotinib exposure; increased plasma concentrations of cobicistat may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is also a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of crizotinib with cobicistat due to increased crizotinib exposure; increased plasma concentrations of cobicistat may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is also a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with crizotinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with crizotinib therapy due to the risk of cobimetinib toxicity. Cobimetinib is a sensitive CYP3A substrate as well as a P-glycoprotein (P-gp) substrate. Crizotinib is a moderate CYP3A4 inhibitor; it also inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Guaifenesin: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Phenylephrine; Promethazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with promethazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation; crizotinib has also been associated with concentration-dependent QT prolongation. (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Promethazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with promethazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation; crizotinib has also been associated with concentration-dependent QT prolongation. (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and crizotinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Crizotinib can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor like crizotinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Conivaptan: (Major) Avoid coadministration of crizotinib with conivaptan due to increased crizotinib exposure. Treatment with crizotinib should be initiated no sooner than 1 week after completion of conivaptan therapy. Crizotinib is a CYP3A substrate. Conivaptan is a strong CYP3A4 inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cyclobenzaprine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of cyclobenzaprine with crizotinib is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Cyclobenzaprine is associated with a possible risk of QT prolongation and torsade de pointes (TdP), particularly in the event of acute overdose. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with crizotinib, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. It is not yet completely clear what effect inhibitors of CYP2B6 or CYP3A4 have on the activation and/or toxicity of cyclophosphamide; it has been postulated that the use of CYP3A4 inhibitors might attenuate neurotoxic effects of the drug in some patients, but no clinically reliable data are available to support this hypothesis. Crizotinib is a moderate CYP3A4 inhibitor, as well as a CYP2B6 inhibitor in vitro. In vitro, coadministration with a CYP3A4 inhibitor had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with both strong and moderate CYP3A4 inhibitors in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Cyclosporine: (Moderate) Monitor cyclosporine serum concentrations if coadministration with crizotinib is necessary and monitor for treatment-related adverse reactions. Exposure to both drugs may increase; adjust the dose of cyclosporine as clinically appropriate. Both crizotinib and cyclosporine are CYP3A4 substrates and moderate inhibitors. Additionally, cyclosporine is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with crizotinib is necessary in patients with CrCL greater than 50 mL/minute. Avoid coadministration in patients with CrCL less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Dabigatran is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function.
    Danazol: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with danazol is necessary. Crizotinib is a CYP3A substrate and danazol is a moderate CYP3A inhibitor.
    Dapagliflozin; Metformin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Darunavir: (Major) Avoid coadministration of crizotinib with darunavir due to increased crizotinib exposure; increased plasma concentrations of darunavir may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Darunavir is a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Darunavir; Cobicistat: (Major) Avoid coadministration of crizotinib with cobicistat due to increased crizotinib exposure; increased plasma concentrations of cobicistat may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is also a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated. (Major) Avoid coadministration of crizotinib with darunavir due to increased crizotinib exposure; increased plasma concentrations of darunavir may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Darunavir is a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of ritonavir and crizotinib is contraindicated due to the potential for increased crizotinib exposure and QT prolongation. Ritonavir is a strong CYP3A4 inhibitor. Crizotinib is a CYP3A4 substrate and has been associated with concentration-dependent QT prolongation. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with crizotinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Dasatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of dasatinib with crizotinib is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Daunorubicin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with daunorubicin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Acute cardiotoxicity can occur during the administration of daunorubicin, although the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with crizotinib. Deflazacort is a CYP3A4 substrate and crizotinib is a moderate inhibitor of CYP3A4. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity.
    Degarelix: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with degarelix. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; QTc prolongation has also been reported with the use of degarelix.
    Delavirdine: (Major) Avoid coadministration of crizotinib with delavirdine due to increased crizotinib exposure; increased plasma concentrations of delavirdine may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor. Delavirdine is a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Desflurane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with halogenated anesthetics. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Desloratadine: (Minor) Concomitant use of crizotinib and desloratadine may result in increased desloratadine concentrations. Crizotinib is a CYP3A4 and P-glycoprotein (PGP) inhibitor, while desloratadine is a PGP substrate. Monitor patients for toxicity with coadministration.
    Desloratadine; Pseudoephedrine: (Minor) Concomitant use of crizotinib and desloratadine may result in increased desloratadine concentrations. Crizotinib is a CYP3A4 and P-glycoprotein (PGP) inhibitor, while desloratadine is a PGP substrate. Monitor patients for toxicity with coadministration.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with crizotinib, assess the QTc interval before and after increasing the dosage of either medication. Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with other drugs known to prolong the QT interval. An interruption of crizotinib therapy, dose reduction, or discontinuation therapy may be necessary. Crizotinib has been associated with concentration-dependent QT prolongation. Clinically relevant QTc prolongation may occur with deutetrabenazine.
    Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of crizotinib with dexamethasone is necessary due to increased dexamethasone exposure. Dexamethasone is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. A strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, increasing the risk of corticosteroid-related side effects.
    Dextromethorphan; Promethazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with promethazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation; crizotinib has also been associated with concentration-dependent QT prolongation.
    Dextromethorphan; Quinidine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with quinidine; an increase in quinidine plasma concentrations may also occur. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Quinidine is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP). Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation.
    Diazepam: (Moderate) Monitor for increased diazepam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary. Diazepam is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
    Digoxin: (Moderate) Monitor digoxin serum concentrations and watch for an increase in digoxin-related adverse reactions if coadministration with crizotinib is necessary. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Dihydroergotamine: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with crizotinib is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and crizotinib is a moderate CYP3A4 inhibitor.
    Diltiazem: (Moderate) Monitor for and hypotension and bradycardia, as well as an increase in crizotinib-related adverse reactions if coadministration with diltiazem is necessary. Crizotinib and diltiazem are both CYP3A substrates and moderate inhibitors. Increased plasma concentrations of both drugs may occur.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Disopyramide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of disopyramide with crizotinib is necessary; an increase in disopyramide-related adverse reactions may also occur. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Disopyramide is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP). Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Cases of life-threatening interactions have been reported for disopyramide when given with other moderate CYP3A4 inhibitors.
    Disulfiram: (Moderate) Monitor for increased disulfiram-related adverse reactions if coadministration with crizotinib is necessary. Crizotinib is a moderate CYP3A4 inhibitor, as well as an in vitro inhibitor of CYP2B6. Disulfiram is primarily metabolized by CYP3A4, and is also a minor substrate of CYP2B6. In a drug interaction study, coadministration with crizotinib increased the AUC of a sensitive CYP3A4 substrate by 3.7-fold. Increased serum concentrations of disulfiram may also occur with concomitant administration.
    Docetaxel: (Minor) Concomitant use of crizotinib and docetaxel may result in increased docetaxel concentrations. Crizotinib is a CYP3A4 and P-glycoprotein (PGP) inhibitor, while docetaxel is a CYP3A4 and PGP substrate. Monitor patients for toxicity with coadministration.
    Dofetilide: (Severe) Because of the potential for torsades de pointes (TdP), concurrent use of dofetilide and crizotinib is contraindicated. Crizotinib has been associated with QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Dolasetron: (Major) Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with dolasetron due to the potential risk of QT prolongation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both crizotinib and dolasetron have been associated with concentration-dependent QT prolongation.
    Donepezil: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of donepezil with crizotinib is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Donepezil; Memantine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of donepezil with crizotinib is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Dorzolamide; Timolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Doxepin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Doxorubicin: (Major) The manufacturer of doxorubicin recommends avoiding coadministration with CYP3A4 inhibitors such as crizotinib, as clinically significant interactions have been reported with these drugs resulting in increased concentration and clinical effect of doxorubicin; QT prolongation may also occur. Monitor ECGs and electrolytes, and watch for doxorubicin-related adverse reactions if coadministration is unavoidable. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Doxorubicin is a major substrate of CYP3A4. Acute cardiotoxicity can occur during administration, although the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Dronabinol, THC: (Moderate) Monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence) if coadministration with crizotinib is necessary. Crizotinib is a moderate CYP3A inhibitor and dronabinol is a CYP3A substrate.
    Dronedarone: (Severe) Because of the potential for torsade de pointes (TdP), use of crizotinib with dronedarone is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Crizotinib has also been associated with concentration-dependent QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as crizotinib. If concomitant use is unavoidable, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Crizotinib is also associated with concentration-dependent QT prolongation.
    Dutasteride; Tamsulosin: (Moderate) Monitor for an increase in tamsulosin-related adverse reactions, including hypotension, if coadministration with crizotinib is necessary. Tamsulosin is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The effects of concomitant administration of a moderate CYP3A4 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
    Edoxaban: (Moderate) Coadministration of edoxaban and crizotinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate crizotinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of crizotinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Major) Consider alternatives to therapy if coadministration of efavirenz with crizotinib is necessary, due to the risk of QT prolongation and torsade de pointes (TdP); an increase in efavirenz-related adverse reactions may also occur. If avoidance is not possible, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Efavirenz is a CYP3A4 substrate that has been associated with QTc prolongation. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Consider alternatives to therapy if coadministration of efavirenz with crizotinib is necessary, due to the risk of QT prolongation and torsade de pointes (TdP); an increase in efavirenz-related adverse reactions may also occur. If avoidance is not possible, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Efavirenz is a CYP3A4 substrate that has been associated with QTc prolongation. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with crizotinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Eletriptan: (Moderate) Monitor for an increase in eletriptan-related adverse reactions if coadministration with crizotinib is necessary. Eletriptan is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased eletriptan exposure by 2-fold to 4-fold.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of crizotinib and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of crizotinib and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily; monitor electrolytes and ECGs for QT prolongation. The coadministration of eliglustat with both crizotinib and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and crizotinib can independently prolong the QT interval, and coadministration increases this risk. Crizotinib is a moderate CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as crizotinib, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
    Empagliflozin; Metformin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with rilpivirine; also monitor for an increase in rilpivirine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with rilpivirine; also monitor for an increase in rilpivirine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with crizotinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with crizotinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Enalapril; Felodipine: (Moderate) Monitor for hypotension and use a conservative approach to felodipine dosing if coadministration with crizotinib is necessary. Felodipine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased felodipine exposure by 2.5-fold and prolonged the half-life by approximately 2-fold.
    Enflurane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with halogenated anesthetics. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; halogenated anesthetics can also prolong the QT interval.
    Enzalutamide: (Major) Avoid coadministration of crizotinib with enzalutamide due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Epirubicin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with epirubicin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    Eplerenone: (Major) If coadministration of crizotinib and eplerenone is necessary, do not exceed an eplerenone dose of 25 mg PO once daily in post-MI patients with heart failure. If coadministered in patients receiving eplerenone for hypertension, initiate eplerenone dosing at 25 mg PO once daily, and increase to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Additionally, check serum potassium and serum creatinine within 3 to 7 days of a patient initiating concomitant treatment due to the increased risk of hyperkalemia, and continue to monitor until the effect of eplerenone is established. If a patient develops hyperkalemia, treatment with eplerenone may be continued after a proper dose adjustment; dose reduction decreases potassium levels. Eplerenone is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A inhibitors increased eplerenone exposure by 100% to 190%.
    Ergotamine: (Moderate) Closely monitor for ergotamine-related adverse reactions, including vasospasm leading to cerebral ischemia and/or ischemia of the extremities, if coadministration with crizotinib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic index and crizotinib is a moderate CYP3A inhibitor. While ergot toxicity has not been reported with moderate CYP3A inhibition, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine.
    Eribulin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with eribulin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have independently been associated with QT prolongation.
    Erythromycin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of erythromycin with crizotinib is necessary; an increase in crizotinib-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) may also occur. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Erythromycin is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP). Crizotinib is a CYP3A substrate that has also been associated with concentration-dependent QT prolongation.
    Erythromycin; Sulfisoxazole: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of erythromycin with crizotinib is necessary; an increase in crizotinib-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) may also occur. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Erythromycin is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP). Crizotinib is a CYP3A substrate that has also been associated with concentration-dependent QT prolongation.
    Escitalopram: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with escitalopram. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation, and escitalopram has additionally been associated with torsade de pointes (TdP).
    Esmolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Estazolam: (Moderate) Monitor for an increase in estazolam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary. Estazolam is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. While in vivo drug interactions have not been conducted between estazolam and CYP3A inhibitors, plasma concentrations of estazolam may increase.
    Ethanol: (Moderate) Patients should avoid regular use of alcohol with crizotinib due to a potential for decreased efficacy of crizotinib. Crizotinib is a CYP3A4 substrate. When used chronically, alcohol induces some CYP isoenzymes, including CYP2E1 and CYP3A4. The effect of moderate CYP3A4 induction on crizotinib has not been studied. Strong CYP3A inducers decreased crizotinib steady-state AUC and Cmax by 84% and 79%, respectively, compared to crizotinib alone. It is possible that a moderate CYP3A4 inducer could also decrease crizotinib exposure. Acute, intermittent ingestion of alcohol does not induce CYP isoenzymes.
    Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with crizotinib is necessary. Ethosuximide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with crizotinib. Crizotinib is a CYP3A4 inhibitor as well as a weak in vitro inhibitor of P-glycoprotein (P-gp); etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Etravirine: (Minor) Monitor for an increase in etravirine-related adverse reactions if coadministration with crizotinib is necessary. Etravirine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Everolimus: (Major) A dose adjustment of everolimus is necessary when prescribed with crizotinib due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. For patients with subependymal giant cell astrocytoma (SEGA) with TSC, the recommended starting dose of Afinitor/Afinitor Disperz is 2.5 mg/m2 once daily, rounded to the nearest tablet strength; subsequent dosing should be guided by therapeutic drug monitoring, with administration every other day if dose reduction is required for patients receiving the lowest available tablet strength. If crizotinib is discontinued, increase everolimus to its original dose after a washout period of 2 to 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Ezogabine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with ezogabine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have independently been associated with QT prolongation.
    Felodipine: (Moderate) Monitor for hypotension and use a conservative approach to felodipine dosing if coadministration with crizotinib is necessary. Felodipine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased felodipine exposure by 2.5-fold and prolonged the half-life by approximately 2-fold.
    Fentanyl: (Moderate) Concomitant use of fentanyl with crizotinib may increase fentanyl plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of crizotinib could decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for both CYP3A4 and P-glycoprotein (P-gp). Crizotinib is a moderate inhibitor of CYP3A4 and an inhibitor of P-gp.
    Fexofenadine: (Minor) Concomitant use of crizotinib and fexofenadine may result in increased fexofenadine concentrations. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while fexofenadine is a P-gp substrate. Monitor patients for toxicity with coadministration.
    Fexofenadine; Pseudoephedrine: (Minor) Concomitant use of crizotinib and fexofenadine may result in increased fexofenadine concentrations. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while fexofenadine is a P-gp substrate. Monitor patients for toxicity with coadministration.
    Fingolimod: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with fingolimod. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Fingolimod initiation results in decreased heart rate and may also prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with flecainide. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Flibanserin: (Severe) The concomitant use of flibanserin and crizotinib is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of crizotinib, start flibanserin at least 2 weeks after the last dose of crizotinib. If initiating crizotinib following flibanserin use, start crizotinib at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Fluconazole: (Severe) The concurrent use of fluconazole with crizotinib is contraindicated due to the risk of QT prolongation; increased crizotinib exposure may also occur. Both fluconazole and crizotinib have been associated with QT prolongation; fluconazole has also been associated with rare cases of torsade de pointes (TdP). Additionally, fluconazole is a moderate inhibitor of CYP3A4 and crizotinib is a CYP3A4 substrate. Fluconazole is contraindicated for coadministration with drugs that are associated with QT prolongation and are also CYP3A4 substrates.
    Fluoxetine: (Major) Monitor for an increase in crizotinib-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) if coadministration with fluoxetine is necessary; also monitor ECGs for QT prolongation and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if the QTc interval is prolonged 500 msec or more or greater than 60 msec change from baseline. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Crizotinib has also been associated with QT prolongation. Additionally, crizotinib is primarily metabolized by CYP3A4/5; fluoxetine is a weak CYP3A4 inhibitor, while its metabolite norfluoxetine is a moderate inhibitor of CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of crizotinib (single dose) by 3.2-fold and 1.4-fold, respectively; weak CYP3A4 inhibitors may also increase crizotinib exposure. The effect of CYP3A4 inhibitors on steady-state crizotinib exposure has not been evaluated.
    Fluoxetine; Olanzapine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with olanzapine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be also associated with a significant prolongation of the QTc interval. (Major) Monitor for an increase in crizotinib-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) if coadministration with fluoxetine is necessary; also monitor ECGs for QT prolongation and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if the QTc interval is prolonged 500 msec or more or greater than 60 msec change from baseline. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Crizotinib has also been associated with QT prolongation. Additionally, crizotinib is primarily metabolized by CYP3A4/5; fluoxetine is a weak CYP3A4 inhibitor, while its metabolite norfluoxetine is a moderate inhibitor of CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of crizotinib (single dose) by 3.2-fold and 1.4-fold, respectively; weak CYP3A4 inhibitors may also increase crizotinib exposure. The effect of CYP3A4 inhibitors on steady-state crizotinib exposure has not been evaluated.
    Fluphenazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with fluphenazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated crizotinib exposure during coadministration of crizotinib and fluvoxamine. Crizotinib has been associated with concentration-dependent QT prolongation. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with other drugs known to prolong the QT interval. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. In addition, crizotinib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration of a single dose of crizotinib with a strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Formoterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Major) Avoid coadministration of crizotinib with fosamprenavir due to increased crizotinib exposure; fosamprenavir exposure may also be increased. Crizotinib is a CYP3A substrate and moderate inhibitor. Amprenavir, the active metabolite of fosamprenavir, is a CYP3A4 substrate and strong CYP3A inhibitor; data also suggest that amprenavir induces CYP3A4. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Fosphenytoin: (Major) Avoid coadministration of crizotinib with fosphenytoin due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Gemifloxacin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; do not exceed the recommended dose, especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Gemifloxacin may prolong the QT interval in some patients, with the maximal change in the QTc occurring approximately 5 to 10 hours following oral administration. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and crizotinib together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Crizotinib therapy interruption, dose reduction, or discontinuation may be necessary for QT prolongation. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and crizotinib as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); crizotinib is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and crizotinib as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); crizotinib is an inhibitor of P-gp.
    Glipizide; Metformin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Glyburide; Metformin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Glycopyrrolate; Formoterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with goserelin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., goserelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with granisetron. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; granisetron has also been associated with QT prolongation.
    Grapefruit juice: (Major) Due to the potential for increased crizotinib exposure and side effects, patients should be advised to avoid intake of grapefruit or grapefruit juice during crizotinib therapy. Crizotinib is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Guanfacine: (Major) Decrease the dose of extended-release guanfacine by 50% if coadministration with crizotinib is necessary; if crizotinib is discontinued, the dose of extended-release guanfacine may be increased to the recommended level. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Recommendations for immediate-release guanfacine are not available. Guanfacine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Halogenated Anesthetics: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with halogenated anesthetics. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with haloperidol; an increase in haloperidol exposure may also occur. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Haloperidol is a CYP3A4 substrate that has been associated with QT prolongation and torsade de pointes (TdP); excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Halothane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with halogenated anesthetics. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; halogenated anesthetics can also prolong the QT interval.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with crizotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Hydroxychloroquine: (Major) Do not administer hydroxychloroquine with crizotinib due to the risk of QT prolongation. Both drugs have been associated with QT prolongation. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine.
    Hydroxyzine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with hydroxyzine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Postmarketing data indicate that hydroxyzine also causes QT prolongation as well as torsade de pointes (TdP).
    Ibrutinib: (Major) If coadministered with crizotinib, initiate ibrutinib therapy at a reduced dose of 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease; monitor patients more frequently for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with crizotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Ibutilide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with ibutilide. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Idarubicin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with idarubicin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Acute cardiotoxicity can occur during the administration of idarubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    Idelalisib: (Major) Avoid coadministration of crizotinib with idelalisib due to increased crizotinib exposure. Crizotinib is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Ifosfamide: (Major) Monitor for a decrease in the clinical efficacy of ifosfamide if coadministration with crizotinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Crizotinib is a moderate CYP3A4 inhibitor. Coadministration may decrease formation of the active metabolites of ifosfamide, decreasing its efficacy.
    Iloperidone: (Major) Avoid coadministration of iloperidone with crizotinib due to the risk of QT prolongation; increased exposure to iloperidone may also occur. Iloperidone is a CYP3A4 substrate that is associated with QT prolongation. Crizotinib is a moderate CYP3A4 inhibitor that also is associated with concentration-dependent QT prolongation. Inhibitors of CYP3A4 can inhibit iloperidone elimination and cause increased blood levels; moderate CYP3A4 inhibitors have not been studied with iloperidone.
    Imatinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with imatinib is necessary. Crizotinib is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor.
    Imipramine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Major) Avoid coadministration of crizotinib with indinavir due to increased crizotinib exposure; plasma concentrations of indinavir may also increase. Crizotinib is a CYP3A substrate and moderate CYP3A4 inhibitor; indinavir is a CYP3A4 substrate and strong CYP3A inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with crizotinib due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. Inotuzumab has been associated with QT interval prolongation. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Irinotecan Liposomal: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration of liposomal irinotecan with crizotinib is necessary. The metabolism of liposomal irinotecan has not been evaluated; however, irinotecan is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may increase exposure to irinotecan.
    Irinotecan: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with crizotinib is necessary. Irinotecan is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Concomitant use may increase exposure to irinotecan.
    Isavuconazonium: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with isavuconazonium is necessary. Crizotinib is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor.
    Isoflurane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with halogenated anesthetics. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; halogenated anesthetics can also prolong the QT interval.
    Isoniazid, INH: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with isoniazid is necessary. Crizotinib is a CYP3A substrate and isoniazid is a moderate CYP3A inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%. (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with isoniazid is necessary. Crizotinib is a CYP3A substrate and isoniazid is a moderate CYP3A inhibitor.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%. (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with isoniazid is necessary. Crizotinib is a CYP3A substrate and isoniazid is a moderate CYP3A inhibitor.
    Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with crizotinib is necessary. Isradipine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
    Itraconazole: (Major) Avoid crizotinib use during and for 2 weeks after discontinuation of itraconazole treatment. Taking these drugs together increases crizotinib exposure; QT prolongation may also occur. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Itraconazole is a strong CYP3A inhibitor that is also associated with QT prolongation. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Ivabradine: (Major) Avoid coadministration of ivabradine and crizotinib as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased the AUC of ivabradine by 2- to 3-fold.
    Ivacaftor: (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Monitor for an increase in ivacaftor-related adverse reactions. Ivacaftor is a CYP3A substrate, and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with crizotinib is necessary; consider the use of an alternative agent to crizotinib that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Major) Avoid coadministration of crizotinib with ketoconazole due to increased crizotinib exposure; QT prolongation may also occur. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ketoconazole is a strong CYP3A inhibitor that is also associated with QT prolongation. Coadministration of a single dose of crizotinib with ketoconazole increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Labetalol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Lapatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with lapatinib; increased lapatinib-related adverse reactions may also occur. Correct hypokalemia or hypomagnesemia prior to administration. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs are associated with concentration-dependent QT prolongation. Lapatinib is also a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Lenvatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with lenvatinib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; QT prolongation was also reported during clinical trials of lenvatinib.
    Leuprolide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with leuprolide. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Leuprolide; Norethindrone: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with leuprolide. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Levalbuterol: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with short-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levobetaxolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Levobunolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Levofloxacin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with levofloxacin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Levofloxacin has been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of levofloxacin. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions and toxicities if coadministration with crizotinib is necessary. Lidocaine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Linagliptin; Metformin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Lithium: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with lithium, as both drugs have been associated with QT prolongation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs.
    Lomitapide: (Severe) Concomitant use of crizotinib and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with crizotinib is unavoidable, lomitapide should be stopped during the course of treatment. Lomitapide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use based on the 27-fold increase in exposure observed with coadministration of a strong CYP3A4 inhibitor.
    Long-acting beta-agonists: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of loperamide with crizotinib is necessary; an increase in other loperamide-related adverse reactions (e.g., CNS effects) may also occur. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. At high doses, loperamide has also been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Additionally, crizotinib is a moderate CYP3A4 inhibitor and loperamide is partially metabolized by CYP3A4 to form N-demethyl loperamide. In an in vitro study, coadministration with a strong CYP3A4 inhibitor significantly inhibited the N-demethylation process by 90%; exposure to loperamide may increase with concomitant crizotinib administration.
    Loperamide; Simethicone: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of loperamide with crizotinib is necessary; an increase in other loperamide-related adverse reactions (e.g., CNS effects) may also occur. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. At high doses, loperamide has also been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Additionally, crizotinib is a moderate CYP3A4 inhibitor and loperamide is partially metabolized by CYP3A4 to form N-demethyl loperamide. In an in vitro study, coadministration with a strong CYP3A4 inhibitor significantly inhibited the N-demethylation process by 90%; exposure to loperamide may increase with concomitant crizotinib administration.
    Lopinavir; Ritonavir: (Severe) Coadministration of ritonavir and crizotinib is contraindicated due to the potential for increased crizotinib exposure and QT prolongation. Ritonavir is a strong CYP3A4 inhibitor. Crizotinib is a CYP3A4 substrate and has been associated with concentration-dependent QT prolongation. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated. (Major) Avoid coadministration of crizotinib with lopinavir due to increased crizotinib exposure; QT prolongation may also occur. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Lopinavir; ritonavir is a strong CYP3A inhibitor that is also associated with QT prolongation. Concomitant use may result in additive QT prolongation. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Lovastatin is a sensitive substrate of CYP3A4 and crizotinib is a moderate CYP3A4 inhibitor.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Lovastatin is a sensitive substrate of CYP3A4 and crizotinib is a moderate CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of crizotinib with lumacaftor; ivacaftor due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and lumacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Lumacaftor; Ivacaftor: (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Monitor for an increase in ivacaftor-related adverse reactions. Ivacaftor is a CYP3A substrate, and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Lurasidone: (Major) The recommended starting dose of lurasidone is 20 mg daily (maximum, 80 mg daily) if coadministration with crizotinib is necessary. Reduce the lurasidone dose to half of its original dose level if crizotinib is added to existing lurasidone therapy. Coadministration with another moderate CYP3A4 inhibitor increased lurasidone exposure by 116%.
    Maprotiline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with maprotiline. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of mefloquine with crizotinib is necessary; an increase in mefloquine-related adverse reactions may also occur. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Mefloquine is a CYP3A substrate. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval, although mefloquine alone has not been reported to cause QT prolongation. Due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine; Promethazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with promethazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation; crizotinib has also been associated with concentration-dependent QT prolongation.
    Mephobarbital: (Major) Avoid coadministration of crizotinib with mephobarbital due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and mephobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Metaproterenol: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with short-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Metformin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Metformin; Pioglitazone: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Metformin; Repaglinide: (Moderate) Monitor blood sugar if coadministration of repaglinide with crizotinib is necessary; an increase in repaglinide-related adverse reactions may occur. Repaglinide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Metformin; Rosiglitazone: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Metformin; Saxagliptin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Metformin; Sitagliptin: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Methadone: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with methadone; carefully consider the risks versus benefits of coadministration. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Methadone is a CYP3A4 substrate considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation.
    Metoprolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Metronidazole: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with metronidazole. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Midazolam: (Moderate) Avoid coadministration of crizotinib with midazolam if possible, due to increased midazolam exposure. If concomitant use is unavoidable, monitor for midazolam-related adverse reactions including sedation and respiratory depression; adjust the dose as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and midazolam is a CYP3A substrate. Coadministration with crizotinib increased the AUC of oral midazolam by 3.7-fold.
    Midostaurin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with midostaurin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. QT prolongation was also reported in patients who received midostaurin in clinical trials.
    Mifepristone, RU-486: (Major) Monitor ECGs for QT prolongation, monitor electrolytes, and monitor for an increase in treatment-related adverse reactions in patients receiving crizotinib concomitantly with mifepristone; to minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Both drugs are CYP3A4 substrates and moderate CYP3A4 inhibitors that have been associated with concentration-dependent QT prolongation.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and crizotinib. Coadminister with caution. Crizotinib has been associated with concentration-dependent QT prolongation. Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with other drugs known to prolong the QT interval. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Major) Avoid coadministration of crizotinib with mitotane due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Moxifloxacin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with moxifloxacin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinolones have also been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nadolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Naloxegol: (Major) Avoid coadministration of crizotinib with naloxegol if possible due to increased naloxegol exposure. If concurrent use is unavoidable, reduce the dose of naloxegol to 12.5 mg once daily and monitor for adverse reactions. Naloxegol is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of naloxegol by 2.86-fold and 3.4-fold, respectively.
    Nebivolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Nebivolol; Valsartan: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Nefazodone: (Major) Avoid coadministration of crizotinib with nefazodone due to increased crizotinib exposure; plasma concentrations of nefazodone may also increase. Crizotinib is a CYP3A substrate and moderate inhibitor. Nefazodone is a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Nelfinavir: (Major) Avoid coadministration of crizotinib with nelfinavir due to increased crizotinib exposure; plasma concentrations of nelfinavir may also increase. Crizotinib is a CYP3A substrate and moderate inhibitor. Nelfinavir is a CYP3A4 substrate and strong inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Neratinib: (Major) Avoid concomitant use of crizotinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Netupitant; Palonosetron: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with netupitant is necessary. Crizotinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
    Nicardipine: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with nicardipine is necessary. Crizotinib is a CYP3A substrate and nicardipine is a moderate CYP3A inhibitor.
    Nifedipine: (Moderate) Monitor for an increase in nifedipine-related adverse reactions, including hypotension, if coadministration with crizotinib is necessary. Nifedipine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
    Nilotinib: (Major) Avoid coadministration of nilotinib with crizotinib if possible due to the risk of concentration-dependent QT prolongation; an increase in treatment-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and electrolytes. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs are CYP3A4 substrates, CYP3A4 moderate inhibitors, and have been associated with QT prolongation. Additionally, nilotinib is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with crizotinib is necessary. Nimodipine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Nintedanib: (Moderate) Closely monitor for nintedanib-related adverse reactions if coadministration with crizotinib is necessary; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for nintedanib patients due to adverse reactions. Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp, and is also a moderate inhibitor of CYP3A4. Coadministration another P-gp/CYP3A4 inhibitor increased exposure to nintedanib by 60%.
    Nisoldipine: (Major) In general, coadministration of nisoldipine with crizotinib should be avoided due to increased nisoldipine exposure. Crizotinib is a moderate CYP3A inhibitor and nisoldipine is a CYP3A substrate.
    Norfloxacin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with norfloxacin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinolones have also been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Monitor electrolytes, ECGs for QT prolongation, and for an increase in crizotinib-related adverse reactions if coadministration with octreotide is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Somatostatin analogs, such as octreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4. Additionally, arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with ofloxacin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinolones have also been associated with a risk of QT prolongation as well as torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with olanzapine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be also associated with a significant prolongation of the QTc interval.
    Olaparib: (Major) Avoid coadministration of olaparib with crizotinib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of olaparib by 121%.
    Olodaterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of ritonavir and crizotinib is contraindicated due to the potential for increased crizotinib exposure and QT prolongation. Ritonavir is a strong CYP3A4 inhibitor. Crizotinib is a CYP3A4 substrate and has been associated with concentration-dependent QT prolongation. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with crizotinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Ondansetron: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with ondansetron. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osimertinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with osimertinib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Concentration-dependent QTc prolongation has been suggested at the recommended dosing of osimertinib in a pharmacokinetic/pharmacodynamic analysis. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Oxaliplatin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with oxaliplatin; correct electrolyte abnormalities prior to administration of oxaliplatin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Ventricular arrhythmias including fatal torsade de pointes (TdP) and QT prolongation have been reported with oxaliplatin use in postmarketing experience.
    Oxybutynin: (Minor) Monitor for oxybutynin-related adverse reactions if coadministration with crizotinib is necessary. Oxybutynin is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Concomitant use with moderate CYP3A4 inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown. The manufacturer of oxybutynin recommends administering with caution.
    Oxycodone: (Moderate) Concomitant use of oxycodone with crizotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of crizotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with crizotinib is necessary. Paclitaxel is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Major) Avoid coadministration of crizotinib with paliperidone if possible due to an increased risk of QT prolongation. If concomitant use is necessary, closely monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation, and paliperidone has also been associated with QT prolongation.
    Panobinostat: (Major) Avoid coadministration of panobinostat with crizotinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for both drugs if QT prolongation occurs. Prolongation of the QT interval has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Pasireotide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with pasireotide. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation; coadministration may have additive effects.
    Pazopanib: (Major) Coadministration of pazopanib with crizotinib is not advised due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation, monitor electrolytes, and monitor for an increase in pazopanib-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation. Additionally, pazopanib is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Penbutolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with systemic pentamidine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both crizotinib and systemic administration of pentamidine have been associated with QT prolongation.
    Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A substrate and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
    Perphenazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with perphenazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with perphenazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) Avoid coadministration of crizotinib with phenobarbital due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Phenylephrine; Promethazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with promethazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation; crizotinib has also been associated with concentration-dependent QT prolongation.
    Phenytoin: (Major) Avoid coadministration of crizotinib with phenytoin due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval such as crizotinib. If avoidance is not possible, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs.
    Pimozide: (Severe) Because of the potential for TdP, use of crizotinib with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP), and crizotinib has also been associated with QT prolongation. Additionally, pimozide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Pindolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Pirbuterol: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with short-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Posaconazole: (Severe) The concurrent use of posaconazole and crizotinib is contraindicated due to the risk of QT prolongation and torsade de pointes (TdP); there is also a risk of increased crizotinib-related adverse reactions. Both crizotinib and posaconazole have been associated with QT prolongation; rare cases of TdP have also occurred with posaconazole usage. Additionally, crizotinib a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Primaquine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with primaquine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; primaquine also has the potential to prolong the QT interval.
    Primidone: (Major) Avoid coadministration of crizotinib with primidone due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Procainamide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with procainamide. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Crizotinib has also been associated with concentration-dependent QT prolongation.
    Prochlorperazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with prochlorperazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with promethazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation; crizotinib has also been associated with concentration-dependent QT prolongation.
    Propafenone: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of propafenone with crizotinib is necessary. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Crizotinib has been associated with concentration-dependent QT prolongation.
    Propranolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Protriptyline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quazepam: (Moderate) Monitor for an increase in quazepam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary. Quazepam is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
    Quetiapine: (Major) The manufacturer of quetiapine recommends avoiding coadministration with other medications that prolong the QT interval, such as crizotinib. . If coadministration cannot be avoided, monitor ECGs and electrolytes. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with quinidine; an increase in quinidine plasma concentrations may also occur. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Quinidine is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP). Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation.
    Quinine: (Major) Avoid concurrent use of crizotinib and quinine due to the risk of QT prolongation and torsade de pointes (TdP); increased exposure to crizotinib may also occur. If coadministration cannot be avoided, monitor ECGs and electrolytes. Crizotinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Quinine is a moderate CYP3A4 inhibitor that has also been associated with QT prolongation and rare cases of TdP.
    Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with crizotinib is necessary; additionally, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs are associated with concentration-dependent QT prolongation; coadministration may result in additive QT prolongation. Additionally, ranolazine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased plasma levels of ranolazine by 100%.
    Regadenoson: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with regadenoson. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Regadenoson has also been associated with QT prolongation.
    Repaglinide: (Moderate) Monitor blood sugar if coadministration of repaglinide with crizotinib is necessary; an increase in repaglinide-related adverse reactions may occur. Repaglinide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Ribociclib: (Major) The manufacturer of ribociclib recommends avoiding coadministration with other medications that may prolong the QT interval, such as crizotinib; an increase in crizotinib-related adverse reactions may also occur. If coadministration cannot be avoided, monitor ECGs and electrolytes. Both drugs are associated with concentration-dependent QT prolongation; in patients treated with ribociclib, these ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, crizotinib is a CYP3A4 substrate and ribociclib is a moderate CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Major) The manufacturer of ribociclib recommends avoiding coadministration with other medications that may prolong the QT interval, such as crizotinib; an increase in crizotinib-related adverse reactions may also occur. If coadministration cannot be avoided, monitor ECGs and electrolytes. Both drugs are associated with concentration-dependent QT prolongation; in patients treated with ribociclib, these ECG changes typically occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, crizotinib is a CYP3A4 substrate and ribociclib is a moderate CYP3A4 inhibitor.
    Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with crizotinib is necessary; this effect may be more significant in patients with hepatic impairment, where there may be an additive effect of reduced metabolism. Rifaximin is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. In vitro exposure to another P-gp inhibitor reduced the efflux ratio of rifaximin by greater than 50%. Coadministration with a P-gp inhibitor in a clinical trial increased the mean AUC of rifaximin by 124-fold.
    Rilpivirine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with rilpivirine; also monitor for an increase in rilpivirine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Risperidone: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with risperidone; the risk is increased in patients with known risk factors for cardiac disease or arrhythmia. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Risperidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP), primarily in the overdosage setting.
    Ritonavir: (Severe) Coadministration of ritonavir and crizotinib is contraindicated due to the potential for increased crizotinib exposure and QT prolongation. Ritonavir is a strong CYP3A4 inhibitor. Crizotinib is a CYP3A4 substrate and has been associated with concentration-dependent QT prolongation. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Rivaroxaban: (Major) Avoid coadministration of rivaroxaban and crizotinib in patients with renal impairment (CrCL 15 to 79 mL/min) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor. Crizotinib is a moderate CYP3A4 inhibitor, and also inhibits P-gp at clinically relevant concentrations. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/min) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/min) compared to patients with normal renal function (CrCL greater than 80 mL/min); similar trends in pharmacodynamic effects were also observed.
    Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with crizotinib is necessary; carefully weigh the risks and benefits of treatment. Roflumilast is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
    Romidepsin: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes at baseline and periodically during treatment in patients receiving crizotinib concomitantly with romidepsin; also monitor for an increase in romidepsin-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Romidepsin is a P-glycoprotein (P-gp) substrate that has been reported to prolong the QT interval. Crizotinib inhibits P-gp at clinically relevant concentrations and has also been associated with concentration-dependent QT prolongation.
    Salmeterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Severe) Concomitant use of saquinavir with crizotinib is contraindicated due to the risk of QT prolongation; plasma concentrations of both drugs may also significantly increase. Crizotinib is a CYP3A4 substrate and moderate inhibitor that has been associated with concentration-dependent QT prolongation. Saquinavir is a CYP3A4 substrate and strong inhibitor, that is also associated with concentration-dependent QT prolongation, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
    Sertraline: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sertraline with crizotinib is necessary. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Sevoflurane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with halogenated anesthetics. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with short-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with crizotinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 140% and 210%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
    Silodosin: (Moderate) Monitor for silodosin-related adverse reactions if coadministration with crizotinib is necessary. Silodosin is a substrate of CYP3A4 and P-glycoprotein (P-gp). Crizotinib is a moderate CYP3A4 inhibitor, and also inhibits P-gp and clinically relevant concentrations. The effect of moderate CYP3A4 inhibitors has not been evaluated; however, plasma concentrations of silodosin may increase based on its interaction with strong CYP3A4 inhibitors. The risk of interaction is increased if the medication also inhibits P-gp.
    Simeprevir: (Major) Concurrent use of crizotinib with simeprevir is not recommended due to increased plasma concentrations of simeprevir. Simeprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Crizotinib is a moderate CYP3A4 inhibitor as well as an inhibitor of P-gp at clinically relevant concentrations. Coadministration with another moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sirolimus: (Major) Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions if coadministration with crizotinib is necessary. The dose of sirolimus may need to be reduced. Sirolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate with a narrow therapeutic range. Crizotinib is a moderate CYP3A4 inhibitor, as well as an inhibitor of P-gp at clinically relevant concentrations. Coadministration with another moderate CYP3A4/P-gp increased the AUC of sirolimus by 2.2-fold.
    Solifenacin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with solifenacin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with concentration-dependent QT prolongation. Torsade de pointes (TdP) has been reported with postmarketing use of solifenacin, although causality was not determined.
    Sonidegib: (Major) Avoid coadministration of sonidegib with crizotinib due to increased plasma concentrations of sonidegib, with may result in increased adverse reactions including musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor for 14 days increased the sonidegib AUC by 1.8-fold; coadministration for 4 months increased the AUC of sonidegib AUC by 2.8-fold.
    Sorafenib: (Major) Closely monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with sorafenib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with sotalol. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Crizotinib has also been associated with concentration-dependent QT prolongation.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of crizotinib with St. John's Wort, Hypericum perforatum due to decreased crizotinib exposure. Crizotinib is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Streptogramins: (Major) Avoid coadministration of crizotinib with dalfopristin; quinupristin due to increased crizotinib exposure. Crizotinib is a CYP3A substrate and quinupristin is a strong CYP3A inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Sufentanil: (Moderate) Concomitant use of sufentanil with crizotinib may increase sufentanil plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of sufentanil until stable drug effects are achieved. Discontinuation of crizotinib could decrease sufentanil plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to sufentanil. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Sufentanil is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with sulfamethoxazole; trimethoprim. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) has also been reported during postmarketing use of sulfamethoxazole; trimethoprim. (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with sulfamethoxazole; trimethoprim. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) has also been reported during postmarketing use of sulfamethoxazole; trimethoprim.
    Sunitinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with sunitinib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Sunitinib can also prolong the QT interval.
    Suvorexant: (Major) When coadministered with crizotinib, the recommended suvorexant dose if 5 mg; if necessary for efficacy the suvorexant dose may be increased to 10 mg. Suvorexant is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased suvorexant exposure by 1.36-fold to 2.05-fold.
    Tacrolimus: (Major) Monitor ECGs for QT prolongation, monitor electrolytes, and frequently monitor tacrolimus whole blood concentrations in patients receiving crizotinib concomitantly with tacrolimus. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Tacrolimus is a CYP3A4 substrate that causes QT prolongation. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with crizotinib is necessary. Tadalafil is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Tamoxifen: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tamoxifen. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Tamsulosin: (Moderate) Monitor for an increase in tamsulosin-related adverse reactions, including hypotension, if coadministration with crizotinib is necessary. Tamsulosin is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The effects of concomitant administration of a moderate CYP3A4 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
    Telavancin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with telavancin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Telavancin has also been associated with QT prolongation.
    Telithromycin: (Major) Avoid coadministration of crizotinib with telithromycin due to increased crizotinib exposure; QT prolongation, torsade de pointes (TdP), and increased exposure to telithromycin may also occur. Crizotinib is a CYP3A substrate and moderate inhibitor that has been associated with concentration-dependent QT prolongation. Telithromycin is a CYP3A4 substrate and strong inhibitor that is associated with both QT prolongation and torsade de pointes (TdP). Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Tenofovir, PMPA: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with crizotinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Terbutaline: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with short-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) According to the manufacturer of tetrabenazine, coadministration with other drugs known to prolong the QTc interval, such as crizotinib, should be avoided. If coadministration cannot be avoided, monitor ECGs and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Crizotinib has been associated with concentration-dependent QT prolongation.
    Thioridazine: (Severe) Because of the potential for torsade de pointes (TdP), use of crizotinib with thioridazine is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and TdP. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Tiagabine: (Moderate) Monitor for an increase in tiagabine-related adverse reactions if coadministration with crizotinib is necessary. It may be useful to obtain plasma concentrations of tiagabine before and after changes are made in the therapeutic regimen, but a therapeutic range has not been established. Tiagabine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Timolol: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with crizotinib is necessary. Tinidazole is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Inhibitors of CYP3A4 inhibitors may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole.
    Tiotropium; Olodaterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Major) Avoid coadministration of crizotinib with tipranavir due to increased crizotinib exposure; plasma concentrations of tipranavir may also increase. Crizotinib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Tizanidine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tizanidine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tizanidine administration may also result in QT prolongation.
    Tolterodine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tolterodine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Tolvaptan: (Major) Avoid coadministration of tolvaptan with crizotinib due to the risk of increased tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Crizotinib is a moderate CYP3A4 inhibitor and is also a P-gp inhibitor at clinical relevant concentrations. The effect of moderate CYP3A inhibitors on tolvaptan exposure has not been assessed, but are expected to lead to substantial increases in tolvaptan plasma concentrations. Coadministration with other P-gp inhibitors has also increased tolvaptan plasma concentrations.
    Topotecan: (Major) Avoid coadministration of oral topotecan with crizotinib due to the risk of increased topotecan exposure; IV topotecan may be administered with crizotinib. Oral topotecan is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. Coadministration with another P-gp inhibitor within 4 hours of oral topotecan increased the dose-normalized AUC of topotecan lactone and total topotecan by 2-fold and 3-fold, respectively.
    Toremifene: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with toremifene. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with crizotinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of crizotinib, a moderate CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate, as well as monitoring for an increase in crizotinib-related adverse reactions, if coadministration of verapamil with crizotinib is necessary. Both verapamil and crizotinib are CYP3A4 substrates and moderate CYP3A4 inhibitors.
    Trazodone: (Major) According to the manufacturer of trazodone, coadministration with other drugs that increase the QT interval, such as crizotinib, should be avoided. If coadministration cannot be avoided, monitor ECGs and electrolytes. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Crizotinib has been associated with concentration-dependent QT prolongation.
    Triazolam: (Moderate) Monitor for an increase in triazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with crizotinib is necessary; consider a dose reduction of triazolam if clinically appropriate. Triazolam is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax of triazolam by 46%, decreased its clearance by 53%, and increased the half-life of triazolam by 35%.
    Tricyclic antidepressants: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with trifluoperazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimethoprim: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with sulfamethoxazole; trimethoprim. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) has also been reported during postmarketing use of sulfamethoxazole; trimethoprim.
    Trimipramine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tricyclic antidepressants (TCAs). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with triptorelin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Umeclidinium; Vilanterol: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with long-acting beta-agonists. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and when associated with hypokalemia or used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with crizotinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for both drugs if QT prolongation occurs. Both drugs can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have also been reported in patients receiving vandetanib.
    Vardenafil: (Major) Due to increased vardenafil exposure, avoid coadministration of vardenafil orally disintegrating tablets with crizotinib; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Additionally, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Vardenafil is a sensitive CYP3A4 substrate that is associated with QT prolongation at both therapeutic and supratherapeutic doses. Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another moderate CYP3A4 inhibitor increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.
    Vemurafenib: (Major) Closely monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with vemurafenib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; vemurafenib has also been associated with QT prolongation.
    Venetoclax: (Major) Avoid coadministration of venetoclax with crizotinib if possible due to increased venetoclax exposure; consider alternative treatments. If concomitant use is unavoidable, reduce the dose of venetoclax by at least 50% and closely monitor for venetoclax-related adverse reactions. Resume the original dose of venetoclax 2 to 3 days after crizotinib is discontinued. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate. Crizotinib is a moderate CYP3A4 inhibitor; it also inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. Coadministration with another P-gp inhibitor increased the Cmax and AUC of venetoclax by 106% and 78%, respectively. Information is not available regarding the magnitude of effect of a moderate CYP3A4 inhibitor.
    Venlafaxine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with venlafaxine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Verapamil: (Moderate) Monitor blood pressure and heart rate, as well as monitoring for an increase in crizotinib-related adverse reactions, if coadministration of verapamil with crizotinib is necessary. Both verapamil and crizotinib are CYP3A4 substrates and moderate CYP3A4 inhibitors.
    Vinblastine: (Moderate) Monitor for increased severity or earlier onset of vinblastine-related adverse reactions if coadministration with crizotinib is necessary. Vinblastine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Enhanced toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
    Vincristine Liposomal: (Major) Avoid coadministration of vincristine with crizotinib due to increased vincristine exposure resulting in an earlier onset and/or increased severity of vincristine-related adverse reactions, including neuromuscular toxicities. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate. Crizotinib is a moderate CYP3A4 inhibitor; it also inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Vincristine: (Major) Avoid coadministration of vincristine with crizotinib due to increased vincristine exposure resulting in an earlier onset and/or increased severity of vincristine-related adverse reactions, including neuromuscular toxicities. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate. Crizotinib is a moderate CYP3A4 inhibitor; it also inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Vinorelbine: (Moderate) Monitor for increased severity or earlier onset of vinorelbine-related adverse reactions if coadministration with crizotinib is necessary. Vinorelbine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Voriconazole: (Major) Avoid coadministration of crizotinib with voriconazole due to increased crizotinib exposure; increased plasma concentrations of voriconazole and QT prolongation may also occur. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Voriconazole is a strong inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Vorinostat: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with vorinostat. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Vorinostat therapy is also associated with a risk of QT prolongation.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with crizotinib is necessary. Crizotinib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Concomitant use of warfarin with CYP3A4 inhibitors may increase the INR.
    Yohimbine: (Moderate) Monitor for an increase in yohimbine-related adverse reactions if coadministration with crizotinib is necessary. Yohimbine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Zileuton: (Minor) Monitor for an increase in zileuton-related adverse reactions if coadministration with crizotinib is necessary. Zileuton is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Although formal drug-drug interaction studies have not been conducted, it is reasonable to monitor these patients clinically.
    Ziprasidone: (Major) Concomitant use of ziprasidone and crizotinib should be avoided due to a potential for additive QT prolongation; ziprasidone plasma concentrations may also increase. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Crizotinib has been associated with concentration-dependent QT prolongation.
    Zolmitriptan: (Moderate) Use caution if coadministration of zolmitriptan with crizotinib is necessary, due to the risk of increased zolmitriptan-related adverse reactions. Zolmitriptan is a CYP3A4 substrate. Crizotinib is a moderate CYP3A4 inhibitor both in vitro and in vivo. Coadministration with crizotinib increased the AUC of a sensitive CYP3A4 substrate by 3.7-fold.
    Zolpidem: (Moderate) Monitor for an increase in zolpidem-related adverse reactions, including excess sedation, if coadministration with crizotinib is necessary. A dose reduction of zolpidem may be necessary. Zolpidem is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during coadministration with some potent inhibitors of CYP3A4.
    Zonisamide: (Moderate) Use caution if coadministration of zonisamide with crizotinib is necessary, due to the risk of increased zonisamide-related adverse reactions; there is also a small possibility of increased crizotinib exposure. Zonisamide is a CYP3A4 substrate. Crizotinib is a moderate CYP3A4 inhibitor both in vitro and in vivo. Coadministration with crizotinib increased the AUC of a sensitive CYP3A4 substrate by 3.7-fold. Additionally, crizotinib is a P-gp substrate in vitro and zonisamide is a weak P-gp inhibitor; exposure to crizotinib may be increased.

    PREGNANCY AND LACTATION

    Pregnancy

    Crizotinib may cause fetal harm based on its mechanism of action and animal studies showing potential for maternal-fetal transmission; however, there are no well-controlled studies in pregnant women. In animal studies, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the maximum recommended doses. Women of childbearing potential should be advised to avoid becoming pregnant while receiving crizotinib and for at least 45 days after discontinuing therapy. When administered to pregnant rats during organogenesis, postimplantation loss was increased at approximately 0.6 times the recommended human dose based on AUC. No teratogenic effects were observed in rats or rabbits at doses up to 2.7 and 1.6 times the recommended human dose based on AUC, respectively; fetal body weights were reduced at both dose levels. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, the patient should be cautioned of the potential hazard to the fetus.

    Counsel patients about the reproductive risk and contraception requirements during crizotinib treatment. Crizotinib can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 45 days after treatment with crizotinib. Men with female partners of reproductive potential should use condoms during treatment with crizotinib and for at least 90 days after the last dose due to a potential for male-mediated teratogenicity. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving treatment should be apprised of the potential hazard to the fetus. In addition, based on animal data, crizotinib may cause infertility in females and males; it is not known whether these effects on fertility are reversible.

    MECHANISM OF ACTION

    Crizotinib is an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins, including the chinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. The formation of ALK fusion proteins results in the activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met. The EML4-ALK fusion gene occurs in 2% to 7% of all non-small cell lung cancers (NSCLC) and is more prevalent in nonsmokers, in patients with a history of light smoking, and in patients with adenocarcinomas.

    PHARMACOKINETICS

    Crizotinib is administered orally. Protein binding in vitro is 91% and is independent of drug concentration. The mean volume of distribution (Vss) is 1,772 L after a 50 mg IV dose, suggesting extensive distribution into the tissues and plasma.
    In vitro studies show that crizotinib is predominantly metabolized by the CYP3A4/5 isoenzyme and the primary metabolic pathways are oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of the O-dealykated metabolites. In single dose studies, the terminal half-life was 42 hours. Single dose studies in healthy subjects demonstrated that 63% of the dose was recovered in the feces and 22% was recovered in the urine. Unchanged drug represented approximately 53% of the dose in the feces and 2.3% of the dose in the urine. The mean apparent clearance was lower at steady state after 250 mg PO twice daily (60 L/h) than after single doses (100 L/h), which is likely due to auto-inhibition of the CYP3A isoenzyme.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2B6, P-glycoprotein (P-gp), OCT1, OCT2
    In vitro and in vivo studies demonstrate that crizotinib is a moderate, time-dependent inhibitor of CYP3A4. In vitro studies also show it is a P-glycoprotein (P-gp) substrate and inhibitor and a CYP2B6 inhibitor. Crizotinib also inhibits the hepatic uptake transporter, organic cation transporter 1 (OCT1), and renal uptake transporter, organic cation transporter 2 (OCT2) at clinically relevant concentrations in vitro. It is unlikely to inhibit the CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 isoenzymes and is unlikely to induce CYP1A2, or CYP3A4. In vitro, it does not inhibit hepatic uptake proteins OATP1B1 or OATP1B3, the hepatic efflux bile salt export pump transporter (BSEP), UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.

    Oral Route

    The mean absolute bioavailability of crizotinib is 43% (range, 32% to 66%) after a single oral dose. The median time to achieve peak concentrations is 4 to 6 hours and steady state is reached within 15 days with a median accumulation ratio of 4.8. Steady state systemic exposure (Cmin and AUC) appears to increase in a greater than dose proportional manner over the dose range of 200 to 300 mg PO twice daily. A high-fat meal reduced the crizotinib AUC and Cmax by approximately 14%; therefore, the manufacturer states that it may be administered with or without food. The aqueous solubility of crizotinib is pH dependent, with a higher pH resulting in a lower solubility. Theoretically, drugs that elevate the gastric pH may decrease the solubility of crizotinib and subsequently reduce its bioavailability.