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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK) and ROS1
    Used in patients with metastatic non-small cell lung cancer that is ALK-positive or ROS1-positive
    Monitor ECGs and electrolytes in patients at increased risk for QT prolongation

    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.
    NOTE: Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    250 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with crizotinib monotherapy significantly improved the primary outcome of progression-free survival (PFS) compared with chemotherapy (pemetrexed or docetaxel) 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 vs. 5.6 months. Overall survival was not improved (20.3 vs. 22.8 months) at an interim analysis; however, 64% of patients randomized to chemotherapy had crossed over to receive crizotinib after disease progression.[45458] Crizotinib also significantly improved median PFS compared with chemotherapy (pemetrexed plus cisplatin or carboplatin) 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 versus 5.3 months, respectively. Overall survival, possibly confounded by a crossover rate of 70% from chemotherapy to crizotinib, was not significantly improved.[58699] Finally, treatment with crizotinib resulted in an ORR of 66% for a median duration of 18.3 months by independent radiology review in a multicenter, single-arm clinical trial in patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC); most responses were partial responses.[45458]

    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:
    Mild hepatic impairment (AST greater than the upper limit of normal (ULN) and total bilirubin less than or equal to ULN, OR total bilirubin 1 to 1.5 times ULN with any AST): No dosage adjustment is necessary.
    Moderate hepatic impairment (total bilirubin 1.5 to 3 times ULN with any AST): The recommended dose of crizotinib is 200 mg PO twice daily.
    Severe hepatic impairment (total bilirubin greater than 3 times ULN with any AST): The recommended dose of crizotinib is 250 mg PO once daily.
     
    Treatment-Related Hepatotoxicity:
    ALT or AST greater than 5 times ULN with total bilirubin 1.5 times ULN or less: Hold crizotinib. When ALT/AST recover to 3 times ULN or less or baseline, resume treatment at the next lower dose (reduce 250mg PO twice daily to 200mg PO twice daily; 200mg PO twice daily to 250mg PO once daily). Permanently discontinue treatment if unable to tolerate crizotinib 250 mg PO once daily.
    ALT or AST greater than 3 times ULN with total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue treatment.

    Renal Impairment

    CrCL 30 mL/min or more: No dose adjustment is recommended.
    CrCL less than 30 mL/min, not requiring dialysis: The recommended dose of crizotinib is 250 mg PO once daily.

    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

    Chronic lung disease (CLD), pneumonitis, pulmonary disease

    Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with crizotinib, generally within the first 3 months of treatment; patients with pulmonary disease or chronic lung disease (CLD) are at increased risk. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. If ILD/pneumonitis is suspected, exclude other causes. Permanently discontinue crizotinib in patients with confirmed treatment-related ILD/pneumonitis.[45458]

    Hepatic disease, hepatotoxicity

    Use crizotinib with caution in patients with pre-existing hepatic disease; fatal drug-induced hepatotoxicity has been reported with crizotinib use. A lower starting dose of crizotinib is recommended for patients with moderate to severe hepatic impairment at baseline. During therapy, increased transaminases generally occurred within the first 2 months of treatment. Monitor liver function tests (LFTs), including AST, ALT, and bilirubin, every 2 weeks for the first 2 months of treatment, then monthly and as clinically indicated. More frequent testing is needed in patients who develop increased transaminases. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be needed for treatment-related increases in LFTs.

    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; avoid crizotinib treatment in patients with congenital long QT syndrome. Symptomatic bradycardia has also been reported in patients treated with crizotinib. 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. Monitor ECGs and electrolytes 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. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary for QT prolongation or bradycardia. Crizotinib should also be used with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, 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.

    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. The onset of vision disorder was typically within the first week of drug administration. 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.[45458]

    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 5.4 times the recommended human dose based on AUC. Other toxicities have not been evaluated.

    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
    anorexia / Delayed / 0-2.0
    esophagitis / Delayed / 0-2.0
    constipation / Delayed / 2.0-2.0
    vomiting / Early / 1.0-2.0
    diarrhea / Early / 0-2.0
    pneumonitis / Delayed / 0.5-1.6
    infection / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    stomatitis / Delayed / 0-1.0
    nausea / Early / 1.0-1.0
    dysphagia / Delayed / 1.0-1.0
    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
    hepatotoxicity / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    optic atrophy / 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
    photophobia / Early / Incidence not known
    photopsia / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    abdominal pain / Early / 26.0-26.0
    dysgeusia / 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 / Early / 9.0-11.0
    rhinitis / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    weakness / Early / Incidence not known
    gonadal suppression / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with crizotinib is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    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 CYP3A 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) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with crizotinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Crizotinib is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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 CYP3A 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.
    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 CYP3A 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) Avoid coadministration of crizotinib with alfuzosin due to the risk of QT prolongation; increased alfuzosin exposure 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 if QT prolongation occurs. Also monitor for evidence of alfuzosin-related adverse effects (e.g., hypotension). Alfuzosin is a CYP3A4 substrate that, based on electrophysiology studies performed by the manufacturer, may prolong the QT interval in a dose-dependent manner. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with a moderate CYP3A4 inhibitor increased the alfuzosin AUC by 1.3-fold.
    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 inhibitor 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 inhibitor 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.
    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.
    Amiodarone: (Major) Avoid coadministration of amiodarone with crizotinib due to the risk of additive QT prolongation and torsade de pointes (TdP); amiodarone exposure may also increase. 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 if QT prolongation occurs. Also monitor for amiodarone-related adverse reactions; consider serial measurement of amiodarone serum concentrations. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Amiodarone, a CYP3A4 substrate and Class III antiarrhythmic agent, is also 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: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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 inhibitor 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 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 inhibitor 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 inhibitor 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 inhibitor 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 inhibitor 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 inhibitor 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 inhibitor 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 inhibitor 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 clarithromycin with crizotinib due to increased plasma concentrations of crizotinib; additive risks of QT prolongation are also possible. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily and monitor electrolytes and ECGs for QT prolongation. An interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary for QT prolongation. Resume the original crizotinib dose after discontinuation of clarithromycin. 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 with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with crizotinib due to increased plasma concentrations of crizotinib; additive risks of QT prolongation are also possible. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily and monitor electrolytes and ECGs for QT prolongation. An interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary for QT prolongation. Resume the original crizotinib dose after discontinuation of clarithromycin. 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 with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Anagrelide: (Major) According to the manufacturer of anagrelide, coadministration with other medications that prolong the QT interval should be avoided. 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.
    Apalutamide: (Major) Avoid coadministration of crizotinib with apalutamide due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and apalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Apomorphine: (Major) Avoid coadministration of crizotinib with apomorphine due to the risk of QT prolongation. 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. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data indicate that QT prolongation is also possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of crizotinib and aprepitant/fosaprepitant 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 CYP3A substrate and a moderate CYP3A inhibitor. Aprepitant is also a CYP3A4 substrate and, 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. Administration with another moderate CYP3A4 inhibitor increased the aprepitant AUC by 2-fold.
    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) Avoid coadministration of crizotinib with aripiprazole due to the risk of QT prolongation. Because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may also occur if the drug is coadministered with moderate inhibitors of CYP3A such as crizotinib. 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. The patient should also be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and 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 a CYP3A4 and 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. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has occurred during therapeutic use of aripiprazole as well as following overdose.
    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 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 CYP3A inhibitor and lumefantrine is a CYP3A4 substrate. The potential for increased lumefantrine concentrations when administered with CYP3A 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 crizotinib with asenapine due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Asenapine has also been associated with QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with crizotinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Crizotinib is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Major) Avoid coadministration of atazanavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of atazanavir. Crizotinib is a CYP3A substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of atazanavir. Crizotinib is a CYP3A substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone. (Major) Avoid coadministration of cobicistat with crizotinib due to increased plasma concentrations of crizotinib; exposure to cobicistat may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of cobicistat. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Atenolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Atenolol; Chlorthalidone: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Atomoxetine: (Major) Avoid coadministration of crizotinib with atomoxetine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has also occurred during therapeutic use of atomoxetine as well as following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of crizotinib with phenobarbital due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving crizotinib. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
    Azithromycin: (Major) Avoid coadministration of crizotinib with azithromycin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Avoid coadministration of crizotinib with bedaquiline due to the risk of QT prolongation. 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. Crizotinib has been associated with concentration-dependent QT prolongation. Bedaquiline has also been reported to prolong the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of crizotinib with phenobarbital due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively. (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) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with crizotinib may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of crizotinib in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A.
    Beta-adrenergic blockers: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Betaxolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of crizotinib with metronidazole due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Potential QT prolongation has also occurred in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of crizotinib with metronidazole due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Potential QT prolongation has also occurred in limited case reports with metronidazole.
    Bisoprolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Bosentan: (Major) Use caution if coadministration of crizotinib with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both crizotinib and a strong or moderate CYP2C9 inhibitor is not recommended. crizotinib is a moderate CYP3A4 inhibitor. Bosentan is a CYP3A4 and CYP2C9 substrate.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and crizotinib as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
    Brexpiprazole: (Moderate) Use caution if coadministration of crizotinib with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and crizotinib are coadministered with a moderate to strong inhibitor of CYP2D6 or if the patient is a poor metabolizer of CYP2D6. If crizotinib is discontinued, adjust the brexpiprazole dosage to its original level. Crizotinib is a moderate CYP3A inhibitor. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of moderate CYP3A4 inhibitors with a strong or moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brigatinib: (Major) Avoid coadministration of brigatinib with crizotinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of crizotinib, resume the brigatinib dose that was tolerated prior to initiation of crizotinib. Brigatinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Brimonidine; Timolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of crizotinib. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; crizotinib is a moderate inhibitor of CYP3A4. Coadministration with another moderate CYP3A4 inhibitor increased bromocriptine exposure by 2.8-fold.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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 CYP3A 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 CYP3A 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 CYP3A inhibitor.
    Buprenorphine: (Major) Avoid coadministration of crizotinib with buprenorphine due to the risk of QT prolongation. Buprenorphine exposure may also increase, resulting in increased or prolonged opioid effects, particularly when crizotinib is added after a stable dose of buprenorphine has been achieved. 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. Consider a dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping crizotinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If crizotinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Buprenorphine is a CYP3A4 substrate that has also 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.
    Buprenorphine; Naloxone: (Major) Avoid coadministration of crizotinib with buprenorphine due to the risk of QT prolongation. Buprenorphine exposure may also increase, resulting in increased or prolonged opioid effects, particularly when crizotinib is added after a stable dose of buprenorphine has been achieved. 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. Consider a dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping crizotinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If crizotinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Buprenorphine is a CYP3A4 substrate that has also 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.
    Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with crizotinib is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and crizotinib is added or removed from therapy. Buspirone is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased buspirone exposure by 3.4 to 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.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with crizotinib. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A4; crizotinib is a moderate inhibitor of CYP3A.
    Carbamazepine: (Major) Avoid coadministration of crizotinib with carbamazepine due to decreased crizotinib exposure; increased carbamazepine exposure may also occur. Both drugs are CYP3A substrates. Crizotinib is also a moderate CYP3A inhibitor and carbamazepine is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carteolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Carvedilol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Ceritinib: (Major) Avoid coadministration of ceritinib with crizotinib due to increased plasma concentrations of crizotinib and the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; 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. Resume the original crizotinib dose after discontinuation of ceritinib. Crizotinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone. Additionally, both drugs are associated with concentration-dependent QT prolongation.
    Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of chloramphenicol. Crizotinib is a CYP3A substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Chloroquine: (Major) Avoid coadministration of crizotinib with chloroquine due to the risk of QT prolongation. 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. Crizotinib has been associated with concentration-dependent QT prolongation. Chloroquine is also 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) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with crizotinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Crizotinib is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with crizotinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Crizotinib is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpromazine: (Major) Avoid coadministration of crizotinib with chlorpromazine due to the risk of QT prolongation. 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. Crizotinib has been associated with concentration-dependent QT prolongation. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Chlorthalidone; Clonidine: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as clonidine, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    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 and crizotinib is a moderate CYP3A inhibitor. Coadministration with a 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) Avoid coadministration of crizotinib with ciprofloxacin due to the risk of QT prolongation; crizotinib exposure may also increase. 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. Also monitor for an increase in crizotinib-related adverse reactions. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ciprofloxacin is a moderate CYP3A4 inhibitor that has had rare cases of QT prolongation and torsade de pointes (TdP) reported 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) Coadministration of crizotinib with citalopram is not recommended due to the risk of QT prolongation. 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 concentration-dependent QT prolongation.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin with crizotinib due to increased plasma concentrations of crizotinib; additive risks of QT prolongation are also possible. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily and monitor electrolytes and ECGs for QT prolongation. An interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary for QT prolongation. Resume the original crizotinib dose after discontinuation of clarithromycin. 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 with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Clofazimine: (Major) Avoid coadministration of crizotinib with clofazimine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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; adjust the dose of clonazepam if necessary. Crizotinib is a moderate CYP3A inhibitor 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.
    Clonidine: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as clonidine, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Clozapine: (Major) Avoid coadministration of crizotinib with clozapine due to the risk of QT prolongation; exposure to clozapine may also increase. If concomitant use is unavoidable, consider a clozapine dose reduction. Monitor ECGs for QT prolongation and monitor electrolytes; also monitor for clozapine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. If crizotinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Clozapine is partially metabolized by CYP3A4, and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Major) Avoid coadministration of cobicistat with crizotinib due to increased plasma concentrations of crizotinib; exposure to cobicistat may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of cobicistat. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with cobimetinib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and cobimetinib is a moderate inhibitor of CYP3A. Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone.
    Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of crizotinib with promethazine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    Codeine; Promethazine: (Major) Avoid coadministration of crizotinib with promethazine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
    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 CYP3A 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.
    Colchicine; Probenecid: (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 CYP3A 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 conivaptan with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose no sooner than 1 week after completion of conivaptan therapy. Crizotinib is a CYP3A substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Cyclosporine: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with crizotinib; additionally, monitor for an increase in crizotinib-related adverse reactions. Use of these medications together may result in elevated serum concentrations of both drugs, causing an increased risk for treatment-related adverse events. Crizotinib Is a CYP3A substrate and moderate inhibitor. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and is also a moderate CYP3A4 inhibitor.
    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.
    Darunavir: (Major) Avoid coadministration of darunavir with crizotinib due to increased plasma concentrations of crizotinib; exposure to darunavir may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of darunavir. Monitor for darunavir-related adverse reactions. Crizotinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with crizotinib due to increased plasma concentrations of crizotinib; exposure to cobicistat may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of cobicistat. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone. (Major) Avoid coadministration of darunavir with crizotinib due to increased plasma concentrations of crizotinib; exposure to darunavir may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of darunavir. Monitor for darunavir-related adverse reactions. Crizotinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with crizotinib due to increased plasma concentrations of crizotinib; exposure to cobicistat may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of cobicistat. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone. (Major) Avoid coadministration of darunavir with crizotinib due to increased plasma concentrations of crizotinib; exposure to darunavir may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of darunavir. Monitor for darunavir-related adverse reactions. Crizotinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of ritonavir. Crizotinib is a CYP3A substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Dasatinib: (Major) Avoid coadministration of crizotinib with dasatinib due to the risk of QT prolongation. 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. Crizotinib has been associated with concentration-dependent QT prolongation. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with crizotinib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; crizotinib is a moderate inhibitor of CYP3A4.
    Degarelix: (Major) Avoid coadministration of crizotinib with degarelix due to the risk of QT prolongation. 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. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QTc interval has also been reported with the use of degarelix.
    Delavirdine: (Major) Avoid coadministration of delavirdine with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of delavirdine. Crizotinib is a CYP3A substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Desflurane: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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).
    Deutetrabenazine: (Major) Avoid coadministration of crizotinib with deutetrabenazine due to the risk of QT prolongation; the risk is higher in patients taking a deutetrabenazine dosage more than 24 mg/day. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes, especially before and after increasing the deutetrabenazine or crizotinib dosage. 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. Clinically relevant QTc prolongation may also 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 CYP3A 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) Avoid coadministration of crizotinib with promethazine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of crizotinib with quinidine due to the risk of QT prolongation; exposure to quinidine may also increase. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
    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 CYP3A inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
    Digoxin: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as digoxin, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor for heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with crizotinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Crizotinib is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    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 CYP3A inhibitor.
    Diltiazem: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as diltiazem, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and diltiazem are both CYP3A substrates and moderate inhibitors.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Major) Avoid coadministration of crizotinib with disopyramide due to the risk of QT prolongation; disopyramide exposure may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; also monitor for an increase in disopyramide-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Disopyramide is a CYP3A4 substrate that is also associated with QT prolongation and torsade de pointes (TdP). Cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate CYP3A4 inhibitors.
    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) Avoid coadministration of crizotinib with dolasetron due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Dolasetron has also been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. 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 if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
    Donepezil: (Major) Avoid coadministration of crizotinib with donepezil due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Avoid coadministration of crizotinib with donepezil due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Dorzolamide; Timolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Doxepin: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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) Avoid coadministration of crizotinib with doxorubicin due to the risk of increased doxorubicin exposure resulting in increased treatment-related adverse reactions. Crizotinib is a moderate CYP3A inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
    Dronabinol: (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) Use caution if coadministration of crizotinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. 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.
    Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and crizotinib during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; crizotinib is also a substrate and moderate inhibitor of CYP3A.
    Efavirenz: (Major) Avoid coadministration of efavirenz with crizotinib due to the risk of QT prolongation; an increase in efavirenz-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 if QT prolongation occurs. Efavirenz is a CYP3A4 substrate that has been associated with QTc prolongation. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of efavirenz with crizotinib due to the risk of QT prolongation; an increase in efavirenz-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 if QT prolongation occurs. Efavirenz is a CYP3A4 substrate that has been associated with QTc prolongation. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of efavirenz with crizotinib due to the risk of QT prolongation; an increase in efavirenz-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 if QT prolongation occurs. Efavirenz is a CYP3A4 substrate that has been associated with QTc prolongation. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with crizotinib. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and crizotinib is a moderate CYP3A inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    Eliglustat: (Major) Avoid coadministration of crizotinib with eliglustat in all patients due to the risk of QT prolongation. If concomitant use is unavoidable in extensive CYP2D6 metabolizers (EMs), reduce the dose of eliglustat to 84 mg PO once daily; monitor ECGs for QT prolongation and monitor electrolytes. In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of crizotinib and eliglustat is not recommended. 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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with crizotinib due to increased plasma concentrations of crizotinib; exposure to cobicistat may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of cobicistat. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with crizotinib due to increased plasma concentrations of crizotinib; exposure to cobicistat may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of cobicistat. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. 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 if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. 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 if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and crizotinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
    Encorafenib: (Major) Avoid coadministration of encorafenib and crizotinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of crizotinib. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If crizotinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of crizotinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Enflurane: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. 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 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 plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with crizotinib in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving concurrent crizotinib, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating crizotinib and periodically thereafter. Eplerenone is a CYP3A4 substrate. Crizotinib is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    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) Avoid coadministration of crizotinib with eribulin due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Avoid coadministration of crizotinib with erythromycin due to the risk of QT prolongation; crizotinib exposure may also increase. If concomitant use is unavoidable, monitor for an increase in crizotinib-related adverse reactions, monitor ECGs for QT prolongation, and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Erythromycin is a moderate CYP3A4 inhibitor that is also associated with QT prolongation and torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of crizotinib with erythromycin due to the risk of QT prolongation; crizotinib exposure may also increase. If concomitant use is unavoidable, monitor for an increase in crizotinib-related adverse reactions, monitor ECGs for QT prolongation, and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Erythromycin is a moderate CYP3A4 inhibitor that is also associated with QT prolongation and torsade de pointes (TdP).
    Escitalopram: (Major) Avoid coadministration of crizotinib with escitalopram due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Escitalopram has also been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Esmolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    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.
    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.
    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 CYP3A 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. If crizotinib is discontinued, increase the everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If crizotinib is discontinued, increase everolimus to its original dose after 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.
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Ezogabine: (Major) Avoid coadministration of crizotinib with ezogabine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Ezogabine has also been associated with QT prolongation.
    Felodipine: (Moderate) Concurrent use of felodipine and crizotinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A inhibitors like crizotinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If crizotinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Fingolimod: (Major) Avoid coadministration of crizotinib with fingolimod due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. 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). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. 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) Avoid coadministration of crizotinib with flecainide due to the risk of QT prolongation. 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 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 that 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) Avoid coadministration of crizotinib with fluoxetine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of crizotinib with fluoxetine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine. (Major) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    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) Avoid coadministration of crizotinib with fluvoxamine due to the risk of QT prolongation; crizotinib exposure may also increase. If concomitant use is unavoidable, monitor for an increase in crizotinib-related adverse reactions; also, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Fluvoxamine is a moderate CYP3A4 inhibitor that has had postmarketing reports of QT prolongation and torsade de pointes (TdP).
    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 fosamprenavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of fosamprenavir. Crizotinib is a CYP3A substrate. Fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Foscarnet: (Major) Avoid coadministration of crizotinib with foscarnet due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of crizotinib with fosphenytoin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Gemifloxacin: (Major) Avoid coadministration of crizotinib with gemifloxacin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of crizotinib with gemtuzumab due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes at baseline and during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Avoid coadministration of crizotinib with gilteritinib due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with crizotinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; monitor with increased frequency in patients at increased risk for QT prolongation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Crizotinib has also been associated with concentration-dependent QT prolongation.
    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) Avoid coadministration of crizotinib with goserelin due to the risk of QT prolongation. 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 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) Avoid coadministration of crizotinib with granisetron due to the risk of QT prolongation. 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 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 with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guanfacine: (Major) Reduce the extended-release (ER) guanfacine dosage to half of the recommended dose if coadministration with crizotinib is necessary. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If crizotinib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Crizotinib may significantly increase guanfacine plasma concentrations.
    Halogenated Anesthetics: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of crizotinib with haloperidol due to the risk of QT prolongation; haloperidol plasma concentrations may also increase. If concomitant use is unavoidable, monitor for an increase in haloperidol-related adverse reactions; also monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Haloperidol is a CYP3A4 substrate that has had reports of QT prolongation and torsade de pointes (TdP) during treatment; excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk. In clinical trials, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
    Halothane: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
    Histrelin: (Major) Avoid coadministration of crizotinib with histrelin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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) Avoid coadministration of crizotinib with hydroxyzine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Postmarketing data indicate that hydroxyzine also causes QT prolongation and torsade de pointes (TdP).
    Ibrutinib: (Major) If coadministered with crizotinib, reduce the ibrutinib dose to 280 mg/day PO for the treatment of B-cell malignancies. Resume ibrutinib at the previous dose if crizotinib is discontinued. Initiate ibrutinib at the recommended dose of 420 mg/day PO for the treatment of chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. Ibrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A 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) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Ibutilide: (Major) Avoid coadministration of crizotinib with ibutilide due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Ibutilide administration can also 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.
    Idelalisib: (Major) Avoid coadministration of idelalisib with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of idelalisib. Crizotinib is a CYP3A substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with crizotinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Crizotinib is a moderate CYP3A inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Major) Avoid coadministration of crizotinib with iloperidone due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Iloperidone has also been associated with QT prolongation.
    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: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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 indinavir with crizotinib due to increased plasma concentrations of crizotinib; plasma concentrations of indinavir may also increase. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; also monitor for indinavir-related adverse reactions. Resume the original crizotinib dose after discontinuation of indinavir. Crizotinib is a CYP3A substrate and moderate inhibitor. Indinavir is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    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.
    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) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    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 due to increased plasma concentrations of crizotinib; QT prolongation may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily. Monitor ECGs for QT prolongation and electrolytes; an interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary for QT prolongation. Resume the original crizotinib dose after discontinuation of itraconazole. 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 with itraconazole increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    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 CYP3A 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. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with crizotinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
    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 CYP3A inhibitor. The effect of moderate CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with crizotinib due to increased plasma concentrations of crizotinib; QT prolongation may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily. Monitor ECGs for QT prolongation and electrolytes; an interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary. Resume the original crizotinib dose after discontinuation of ketoconazole. 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 with ketoconazole increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively.
    Labetalol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Lapatinib: (Major) Avoid coadministration of crizotinib with lapatinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Both drugs have been associated with concentration-dependent QT prolongation. Ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with crizotinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Crizotinib has been associated with concentration-dependent QT prolongation.
    Letermovir: (Moderate) Administering letermovir with crizotinib may increase crizotinib concentration and risk for adverse events. Avoid coadministration if the patient is also receiving cyclosporine, because the magnitude of this interaction may be increased. Crizotinib is predominately metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Leuprolide: (Major) Avoid coadministration of crizotinib with leuprolide due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of crizotinib with leuprolide due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    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) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Levobunolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Levofloxacin: (Major) Avoid coadministration of crizotinib with levofloxacin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Levofloxacin has been associated with a risk of QT prolongation; although extremely rare, torsade de pointes has been reported during postmarketing surveillance of levofloxacin.
    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 CYP3A inhibitor.
    Lithium: (Major) Avoid coadministration of crizotinib with lithium due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of crizotinib with lofexidine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Lofexidine also prolongs the QT interval.
    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) Avoid coadministration of crizotinib with loperamide due to the risk of QT prolongation; exposure to loperamide may also increase. If concomitant use is unavoidable, monitor for loperamide-related adverse reactions; also monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Loperamide is a CYP3A4 substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Major) Avoid coadministration of crizotinib with loperamide due to the risk of QT prolongation; exposure to loperamide may also increase. If concomitant use is unavoidable, monitor for loperamide-related adverse reactions; also monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Loperamide is a CYP3A4 substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with crizotinib due to increased plasma concentrations of crizotinib; QT prolongation may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily. Monitor ECGs for QT prolongation and electrolytes. Resume the original crizotinib dose after discontinuation of lopinavir. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Lopinavir is a strong CYP3A inhibitor that is also associated with QT prolongation. Concomitant use may result in additive QT prolongation. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone. (Major) Avoid coadministration of ritonavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of ritonavir. Crizotinib is a CYP3A substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    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 CYP3A 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 CYP3A inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of crizotinib with lumacaftor; ivacaftor due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Lumacaftor; Ivacaftor: (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. 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. Lurasidone is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased lurasidone exposure by 116%.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as crizotinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Crizotinib has been associated with concentration-dependent QT prolongation.
    Maprotiline: (Major) Avoid coadministration of crizotinib with maprotiline due to the risk of QT prolongation. 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 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) Avoid coadministration of crizotinib with mefloquine due to the risk of QT prolongation; exposure to mefloquine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; also monitor for an increase in mefloquine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Mefloquine is a CYP3A4 substrate. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, 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) Avoid coadministration of crizotinib with promethazine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Mephobarbital: (Major) Avoid coadministration of crizotinib with mephobarbital due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    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; 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 CYP3A inhibitor.
    Methadone: (Major) Avoid coadministration of crizotinib with methadone due to the risk of QT prolongation; exposure to methadone may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. If crizotinib is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. 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 (greater than 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 CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If crizotinib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Metoprolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Metronidazole: (Major) Avoid coadministration of crizotinib with metronidazole due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Potential QT prolongation has also occurred in limited case reports with metronidazole.
    Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions (e.g., sedation, respiratory depression) if coadministration with crizotinib is necessary. Midazolam is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with crizotinib increased midazolam exposure by 3.7-fold.
    Midostaurin: (Major) Avoid coadministration of crizotinib with midostaurin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Avoid coadministration of crizotinib with mifepristone due to the risk of QT prolongation and increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily and always use the lowest effective dose of mifepristone. Monitor ECGs for QT prolongation and monitor electrolytes; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Resume the original crizotinib dose after discontinuation of mifepristone. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Mifepristone is a strong CYP3A4 inhibitor that has also been associated with dose-dependent prolongation of the QT interval. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Mirtazapine: (Major) Avoid coadministration of crizotinib with mirtazapine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid coadministration of crizotinib with mitotane due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Moxifloxacin: (Major) Avoid coadministration of crizotinib with moxifloxacin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (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) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with crizotinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and crizotinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
    Nebivolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Nebivolol; Valsartan: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Nefazodone: (Major) Avoid coadministration of nefazodone with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of nefazodone. Crizotinib is a CYP3A substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Nelfinavir: (Major) Avoid coadministration of nelfinavir with crizotinib due to increased plasma concentrations of crizotinib; plasma concentrations of nelfinavir may also increase. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; also monitor for an increase in nelfinavir-related adverse reactions. Resume the original crizotinib dose after discontinuation of nelfinavir. Crizotinib is a CYP3A substrate and moderate inhibitor. Nelfinavir is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    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 CYP3A 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, Fosnetupitant; 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.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib 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 crizotinib with nilotinib due to the risk of QT prolongation; exposure to crizotinib may also increase. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy; nilotinib is also a moderate CYP3A4 inhibitor. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation.
    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 CYP3A inhibitor.
    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.
    Nortriptyline: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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) Avoid coadministration of crizotinib with octreotide due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (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. Until further data are available, it is suggested to use octreotide cautiously in patients receiving drugs which prolong the QT interval.
    Ofloxacin: (Major) Avoid coadministration of crizotinib with ofloxacin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinolones have been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (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) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be 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 CYP3A 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: (Major) Avoid coadministration of ritonavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of ritonavir. Crizotinib is a CYP3A substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Ondansetron: (Major) Avoid coadministration of crizotinib with ondansetron due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osimertinib: (Major) Avoid coadministration of crizotinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib; crizotinib has been associated with concentration-dependent QT prolongation.
    Oxaliplatin: (Major) Avoid coadministration of crizotinib with oxaliplatin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin 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 CYP3A 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) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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 CYP3A 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 the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Paliperidone has also been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
    Panobinostat: (Major) Coadministration of crizotinib with panobinostat is not recommended due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has also been reported with panobinostat.
    Pasireotide: (Major) Avoid coadministration of crizotinib with pasireotide due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Avoid coadministration of crizotinib with pazopanib due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Pazopanib has also been reported to prolong the QT interval.
    Penbutolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Avoid coadministration of crizotinib with systemic pentamidine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Systemic pentamidine has also 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 inhibitor 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: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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 plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of crizotinib with promethazine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of crizotinib with phenytoin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Pimavanserin: (Major) Avoid coadministration of crizotinib with pimavanserin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Pimavanserin may also cause QT prolongation.
    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) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    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) Avoid coadministration of crizotinib with primaquine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Primaquine may also cause QT interval prolongation.
    Primidone: (Major) Avoid coadministration of crizotinib with primidone due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Procainamide: (Major) Avoid coadministration of crizotinib with procainamide due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Procainamide is also associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    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) Avoid coadministration of crizotinib with promethazine due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of crizotinib with propafenone due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Propranolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Protriptyline: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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) Avoid coadministration of crizotinib with quetiapine due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Avoid coadministration of crizotinib with quinidine due to the risk of QT prolongation; exposure to quinidine may also increase. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
    Quinine: (Major) Avoid coadministration of crizotinib with quinine due to the risk of QT prolongation; exposure to both drugs may also increase. Crizotinib is a CYP3A substrate and moderate inhibitor that has been associated with concentration-dependent QT prolongation. Quinine is a CYP3A4 substrate and inhibitor (strength unknown) that has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Major) Avoid coadministration of crizotinib with ranolazine due to the risk of QT prolongation. If concomitant use is unavoidable, limit the dose of ranolazine to 500 mg twice daily and monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Ranolazine is a CYP3A4 substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Coadministration with other moderate CYP3A4 inhibitors increased ranolazine exposure by 50% to 130%.
    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 CYP3A inhibitor.
    Ribociclib: (Major) Avoid coadministration of ribociclib with crizotinib due to increased plasma concentrations of crizotinib and the risk of QT prolongation. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ribociclib is a strong CYP3A inhibitor that is also associated with concentration-dependent QT prolongation. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with crizotinib due to increased plasma concentrations of crizotinib and the risk of QT prolongation. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ribociclib is a strong CYP3A inhibitor that is also associated with concentration-dependent QT prolongation. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Rilpivirine: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. 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 if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
    Risperidone: (Major) Avoid coadministration of crizotinib with risperidone due to the risk of QT prolongation. 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 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 overdose setting.
    Ritonavir: (Major) Avoid coadministration of ritonavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of ritonavir. Crizotinib is a CYP3A substrate. ritonavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    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 CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
    Romidepsin: (Moderate) Avoid coadministration of crizotinib with romidepsin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Romidepsin has also been reported to prolong the QT interval.
    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: (Major) Avoid coadministration of crizotinib with sertraline due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. There have also been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Sevoflurane: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. 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 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; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, 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. Crizotinib is a moderate CYP3A inhibitor. 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.
    Simeprevir: (Major) Concurrent use of crizotinib with simeprevir is not recommended due to increased plasma concentrations of simeprevir. Simeprevir is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving crizotinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Crizotinib has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and crizotinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sirolimus: (Moderate) 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 substrate with a narrow therapeutic range. Crizotinib is a moderate CYP3A inhibitor.
    Solifenacin: (Major) Avoid coadministration of crizotinib with solifenacin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Solifenacin has also been associated with dose-dependent prolongation of the QT interval; torsade de pointes (TdP) has been reported with postmarketing use, 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 CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
    Sorafenib: (Major) Avoid coadministration of crizotinib with sorafenib due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Avoid coadministration of crizotinib with sotalol due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. 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.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of crizotinib with St. John's Wort due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if crizotinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like crizotinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If crizotinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sunitinib: (Major) Avoid coadministration of crizotinib with sunitinib due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Sunitinib can also prolong the QT interval.
    Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with crizotinib. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
    Tacrolimus: (Major) Avoid coadministration of crizotinib with tacrolimus due to the risk of QT prolongation; exposure to tacrolimus may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. Frequently monitor tacrolimus whole blood concentrations; adjust the dose of tacrolimus as clinically appropriate. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Tacrolimus is a sensitive CYP3A4 substrate that also causes 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 CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Tamoxifen: (Major) Avoid coadministration of crizotinib with tamoxifen due to the risk of QT prolongation. 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 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 been described when tamoxifen is used at lower doses.
    Tamsulosin: (Moderate) Use caution if coadministration of crizotinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. 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) Avoid coadministration of crizotinib with telavancin due to the risk of QT prolongation. 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 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 telithromycin with crizotinib due to increased plasma concentrations of crizotinib; QT prolongation, torsade de pointes (TdP), and increased exposure to telithromycin may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily. Monitor ECGs for QT prolongation and monitor electrolytes; additionally, watch for treatment-related adverse reactions. Resume the original crizotinib dose after discontinuation of telithromycin. 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 with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    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) Avoid coadministration of crizotinib with tetrabenazine due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Tetrabenazine also causes a small increase in the corrected QT interval (QTc).
    Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with crizotinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor 100 mg/ivacaftor 150 mg tablet every other day in the morning and 1 ivacaftor 150 mg tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor 150 mg should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); crizotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    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 CYP3A inhibitor.
    Timolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    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 CYP3A 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 tipranavir with crizotinib due to increased plasma concentrations of crizotinib. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily; resume the original crizotinib dose after discontinuation of tipranavir. Crizotinib is a CYP3A substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Tolterodine: (Major) Avoid coadministration of crizotinib with tolterodine due to the risk of QT prolongation. 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 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 crizotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with crizotinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Toremifene: (Major) Avoid coadministration of crizotinib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. An interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary if QT prolongation occurs. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Crizotinib has also been associated with concentration-dependent QT prolongation.
    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 CYP3A 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: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as verapamil, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and verapamil are both CYP3A substrates and moderate inhibitors.
    Trazodone: (Major) Avoid coadministration of crizotinib with trazodone due to the risk of QT prolongation and torsade de pointes (TdP). Crizotinib has been associated with concentration-dependent QT prolongation. Trazodone can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP with trazodone use.
    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 CYP3A 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: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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.
    Trimipramine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib 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) Avoid coadministration of crizotinib with triptorelin due to the risk of QT prolongation. 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 if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., triptorelin) also 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 CYP3A 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) Avoid coadministration of crizotinib with vemurafenib due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Vemurafenib has also been associated with QT prolongation.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with crizotinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of crizotinib. Venetoclax is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Venlafaxine: (Major) Avoid coadministration of crizotinib with venlafaxine due to the risk of QT prolongation. 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 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) was reported with postmarketing use.
    Verapamil: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as verapamil, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and verapamil are both CYP3A substrates and moderate 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 CYP3A 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 substrate and crizotinib is a moderate CYP3A inhibitor.
    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 substrate and crizotinib is a moderate CYP3A inhibitor.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with crizotinib is necessary. Vinorelbine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Voriconazole: (Major) Avoid coadministration of voriconazole with crizotinib due to increased plasma concentrations of crizotinib; QT prolongation may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily. Monitor ECGs for QT prolongation and monitor electrolytes; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Resume the original crizotinib dose after discontinuation of voriconazole. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    Vorinostat: (Major) Avoid coadministration of crizotinib with vorinostat due to the risk of QT prolongation. 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 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 CYP3A 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 CYP3A 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 CYP3A 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 the potential for additive QT prolongation. 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. 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.

    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.

    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.

    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 geometric mean volume of distribution (Vss) is 1,772 L after a single IV dose. In single dose studies, the mean apparent terminal half-life was 42 hours. Single dose studies in healthy subjects demonstrated that 63% of the dose was recovered in the feces (53% as unchanged drug) and 22% was recovered in the urine (2.3% as unchanged drug). The mean apparent clearance of crizotinib was lower at steady state after 250 mg PO twice daily (60 L/h) than after single doses (100 L/h).[45458]
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2B6, P-glycoprotein (P-gp)
    Crizotinib is predominantly metabolized by CYP3A4; it is also a substrate of P-gp in vitro. It is a moderate CYP3A4 inhibitor, as well as an in vitro inhibitor of CYP2B6, P-gp, OCT1, and OCT2.[45458]

    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 (Tmax) 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. No clinically significant differences in crizotinib pharmacokinetics were observed when used concomitantly with a proton pump inhibitor.[45458]