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  • CLASSES

    Small Molecule Antineoplastic Anaplastic Lymphoma Kinase (ALK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    An oral kinase inhibitor, primarily targeting anaplastic lymphoma kinase (ALK)
    Used for the treatment of ALK-positive, metastatic non-small cell lung cancer
    Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions

    COMMON BRAND NAMES

    Zykadia

    HOW SUPPLIED

    Ceritinib Oral Tab: 150mg
    Zykadia Oral Cap: 150mg

    DOSAGE & INDICATIONS

    For the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC).
    NOTE: Patients should be selected based on the presence of ALK positivity in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements is available at http://www.fda.gov/CompanionDiagnostics.
    For the treatment of ALK-positive metastatic NSCLC in patients who have progressed on or are intolerant to crizotinib.
    Oral dosage
    Adults

    450 mg orally once daily with food until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, single-arm, open-label clinical trial, patients with ALK-positive, metastatic NSCLC who progressed or were intolerant to crizotinib (n = 163) had an objective response rate of 43.6% (partial response, 41.1%; complete response, 2.5%) as evaluated by a blinded independent central review committee. The duration of response was 7.1 months.

    For the first-line treatment of ALK-positive metastatic NSCLC.
    Oral dosage
    Adults

    450 mg orally once daily with food until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label phase 3 clinical trial, treatment with ceritinib (n = 175) significantly improved PFS as assessed by a blinded independent review committee in patients with previously untreated ALK-rearranged metastatic NSCLC compared with platinum-based chemotherapy plus pemetrexed, followed by pemetrexed maintenance therapy (n = 189) (16.6 months vs. 8.1 months); the overall response rate was 73% vs. 27%, respectively (partial response, 72% vs. 27%). Overall survival, while not mature, was not significantly improved (not estimable vs. 26.2 months); however, this may have been confounded by 72% of chemotherapy patients receiving treatment with ceritinib after progression. In patients with measurable intracranial disease at baseline, the overall response rate was higher with ceritinib (n = 28) versus chemotherapy (n = 27) (57% vs. 22%), with partial responses in 50% versus 15% of patients, respectively.

    MAXIMUM DOSAGE

    Adults

    450 mg PO once daily with food.

    Geriatric

    450 mg PO once daily with food.

    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 to moderate hepatic impairment (Child-Pugh A or B): No dose adjustment is recommended.
    Severe hepatic impairment (Child-Pugh C): Reduce the starting dose of ceritinib by approximately one-third, rounded to the nearest multiple of the 150-mg dosage strength.
     
    Treatment-Related Hepatotoxicity:
    Total bilirubin 2 times the upper limit of normal (ULN) or less, and ALT/AST greater than 5 times ULN: Hold ceritinib therapy. When ALT/AST levels return to baseline or less than or equal to 3 times ULN, resume ceritinib therapy at the next lower dose; do not resume therapy in patients unable to tolerate 150 mg once daily with food.
    Total bilirubin greater than 2 times ULN in the absence of cholestasis or hemolysis, and ALT/AST greater than 3 times ULN: Permanently discontinue ceritinib treatment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take ceritinib with food.
    Swallow whole; do not crush or cut.
    Do not take with grapefruit or grapefruit juice.
    If a dose is missed, make it up unless the next dose is due within 12 hours. Do not take 2 doses at the same time if a dose is missed.
    If vomiting occurs, do not take an additional dose. Take the next dose at the next scheduled time.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease, hepatotoxicity

    Use ceritinib with caution in patients with pre-existing hepatic disease; dosage adjustments are necessary for patients with severe (Child-Pugh C) baseline hepatic impairment. Additionally, drug-induced hepatotoxicity has been reported in patients treated with ceritinib. Monitor liver function tests, including ALT, AST, and total bilirubin, once monthly and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. An interruption of therapy, dosage adjustment, or discontinuation of therapy may be necessary for patients who develop hepatotoxicity.[57094]

    Pneumonitis, pulmonary disease

    Use ceritinib with caution in patients with pre-existing pulmonary disease; severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis has been reported in patients treated with ceritinib. Monitor patients for signs or symptoms (e.g., new or worsening chest pain or shortness of breath) of pneumonitis. Exclude other potential causes of ILD/pneumonitis and permanently discontinue ceritinib therapy in patients diagnosed with treatment-related ILD/pneumonitis.

    Diabetes mellitus, hyperglycemia

    Use ceritinib with caution in patients with pre-existing diabetes mellitus or glucose intolerance, as hyperglycemia has been reported in patients treated with ceritinib across clinical trials. Monitor fasting blood glucose levels in all patients prior to the start of treatment, and periodically thereafter as indicated; treat medically as necessary. An interruption of therapy, dose adjustment, or discontinuation may be necessary for patients who develop hyperglycemia that cannot be medically managed.[57094]

    Bradycardia

    Bradycardia has occurred in patients treated with ceritinib in clinical trials. Avoid coadministration of ceritinib with other agents known to cause bradycardia to the extent possible due to the risk of additive bradycardia. Monitor blood pressure and heart rate regularly. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary.[57094]

    Alcoholism, cardiac arrhythmias, cardiac disease, coronary artery disease, electrolyte imbalance, females, geriatric, heart failure, hypertension, hypocalcemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease, torsade de pointes, ventricular arrhythmias

    If possible, avoid use of ceritinib in patients with congenital long QT syndrome. Concentration-dependent QT prolongation has been reported with ceritinib use, which increases the risk of Torsade de pointes (TdP), ventricular arrhythmias, or sudden death. Use caution and periodically monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias (bradycardia), electrolyte imbalance, or those who are taking medications that are known to prolong the QTc interval. Because strong CYP3A4 inhibitors may increase the risk of a prolonged QT interval, these agents should be avoided if possible. Evaluate ECGs and electrolytes periodically during therapy. Correct electrolyte abnormalities prior to starting ceritinib. Additionally, use ceritinib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, 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. Ceritinib treatment interruption, dosage adjustment, or treatment discontinuation may be necessary in patients who develop QT prolongation.

    Pancreatitis

    Use ceritinib with caution in patients with a history of pancreatitis; pancreatitis and grade 3 or 4 elevations in pancreatic enzymes have occurred with ceritinib therapy in clinical trials. Monitor lipase and amylase prior to starting therapy with ceritinib, and periodically thereafter as indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during ceritinib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, ceritinib can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who become pregnant while receiving ceritinib should be apprised of the potential hazard to the fetus. An embryo-fetal development study in pregnant rats and rabbits found dose-related skeletal anomalies including delayed ossifications and skeletal variations after ceritinib exposure less than 0.5-fold and 0.015-fold the human exposure by AUC at the recommended dose, respectively. At 0.13-fold the human exposure by AUC at the recommended dose, a low incidence of visceral anomalies including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery occurred in pregnant rabbits. Maternal toxicity, abortion, and embryolethality were also reported with higher exposures in animal studies.

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

    Counsel patients about the reproductive risk and contraception requirements during ceritinib treatment. Ceritinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with ceritinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of ceritinib. Based on the potential for male-mediated teratogenicity, males with female partners of reproductive potential should use condoms during treatment with ceritinib and for 3 months after the last dose. Women who become pregnant while receiving ceritinib or while their partner is receiving ceritinib should be apprised of the potential hazard to the fetus. There are no data regarding the effect of ceritinib on human fertility. In general toxicology studies conducted in monkeys and rats at exposures greater than or equal to 0.5-fold and 1.5-fold, respectively of the human exposure at the recommended dose, there were no adverse effects on male or female reproductive organs.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from ceritinib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether ceritinib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 13.0-49.0
    hyperglycemia / Delayed / 10.0-13.0
    visual impairment / Early / 4.0-9.0
    hyperamylasemia / Delayed / 7.0-8.0
    asthenia / Delayed / 5.0-7.0
    fatigue / Early / 5.0-7.0
    hypophosphatemia / Delayed / 3.7-7.0
    abdominal pain / Early / 1.1-6.0
    diarrhea / Early / 1.1-6.0
    QT prolongation / Rapid / 1.3-6.0
    vomiting / Early / 0-5.0
    anemia / Delayed / 4.2-5.0
    nausea / Early / 0-4.0
    bradycardia / Rapid / 1.1-4.0
    infection / Delayed / 0-4.0
    renal failure (unspecified) / Delayed / 2.0-4.0
    weight loss / Delayed / 0-3.7
    neutropenia / Delayed / 2.1-2.1
    pericardial effusion / Delayed / 2.0-2.0
    back pain / Delayed / 1.6-1.6
    pericarditis / Delayed / 1.6-1.6
    pneumonitis / Delayed / 1.5-1.5
    anorexia / Delayed / 1.0-1.1
    rash / Early / 0-1.1
    dizziness / Early / 1.1-1.1
    hyperbilirubinemia / Delayed / 0.5-1.0
    pancreatitis / Delayed / 0-1.0
    thrombocytopenia / Delayed / 1.0-1.0
    pruritus / Rapid / 0-0.5
    musculoskeletal pain / Early / 0.5-0.5
    headache / Early / 0.5-0.5
    seizures / Delayed / 2.0
    dehydration / Delayed / 2.0
    GI bleeding / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 20.0-29.0
    dysphagia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hypotonia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    photopsia / Delayed / Incidence not known

    Mild

    cough / Delayed / 0-25.0
    fever / Early / 19.0-19.0
    gastroesophageal reflux / Delayed / Incidence not known
    dyspepsia / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    weakness / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with ceritinib is necessary. Dolutegravir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Abemaciclib: (Major) If coadministration with ceritinib is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If ceritinib is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of ceritinib. Abemaciclib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and ceritinib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Acebutolol: (Major) Avoid coadministration of ceritinib with acebutolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; acebutolol also causes bradycardia.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ceritinib 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 ceritinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ceritinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Dihydrocodeine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. If ceritinib 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 strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib 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 ceritinib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Aclidinium; Formoterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Ado-Trastuzumab emtansine: (Major) Avoid coadministration of ceritinib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ceritinib has cleared from the circulation (approximately 3 half-lives of ceritinib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ceritinib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Albuterol: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib is necessary. If ceritinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ceritinib 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 ceritinib 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: (Severe) Alfuzosin is contraindicated for use with ceritinib due to the potential for serious/life-threatening reactions, including hypotension. Additive effects on the QT interval may also occur. Alfuzosin is a CYP3A4 substrate that may prolong the QT interval in a dose-dependent manner. Ceritinib is a strong CYP3A4 inhibitor that also causes concentration-dependent QT prolongation. Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
    Aliskiren; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with ceritinib is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and ceritinib should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
    Alosetron: (Moderate) Concomitant use of alosetron with ceritinib may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; ceritinib is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
    Alprazolam: (Major) Avoid coadministration of alprazolam and ceritinib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ceritinib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
    Amiodarone: (Major) Avoid coadministration of amiodarone with ceritinib if possible due to the risk of QT prolongation; exposure to amiodarone may also be increased. Because amiodarone has an extremely long half-life, an interaction is possible for days to weeks after discontinuation of amiodarone. If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; also consider serial measurement of amiodarone serum concentrations. An interruption of ceritinib therapy, dose reduction, or discontinuation of ceritinib therapy may be necessary if QT prolongation occurs. Amiodarone, a Class III antiarrhythmic agent, is a CYP3A4 substrate associated with a well-established risk of QT prolongation; although the frequency of torsade de pointes (TdP) is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Ceritinib is a strong CYP3A4 inhibitor associated with concentration-dependent QT prolongation.
    Amitriptyline: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and amitriptyline; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of chlordiazepoxide with ceritinib is necessary. Chlordiazepoxide is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and amitriptyline; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Atorvastatin: (Major) Consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness) if coadministration of atorvastatin with ceritinib is required, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ceritinib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration of ceritinib with atorvastatin may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Telmisartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of ceritinib with clarithromycin due to the risk of QT prolongation and increased ceritinib exposure. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, further dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After clarithromycin is discontinued, resume the dose of ceritinib taken prior to initiating clarithromycin. Ceritinib is a CYP3A4 substrate that causes concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that is also associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of ceritinib with clarithromycin due to the risk of QT prolongation and increased ceritinib exposure. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, further dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After clarithromycin is discontinued, resume the dose of ceritinib taken prior to initiating clarithromycin. Ceritinib is a CYP3A4 substrate that causes concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that is also associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Anagrelide: (Major) Do not use anagrelide with ceritinib due to the risk of QT prolongation. 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. Concentration-dependent QT prolongation has also been reported with ceritinib.
    Apalutamide: (Major) Avoid coadministration of ceritinib with apalutamide due to decreased ceritinib exposure, resulting in decreased efficacy of treatment; exposure to apalutamide may also increase. Both drugs are CYP3A4 substrates. Ceritinib is also a strong CYP3A4 inhibitor and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Apomorphine: (Major) Avoid coadministration of ceritinib with apomorphine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Limited data indicate that QT prolongation is possible with apomorphine administration; however, the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of ceritinib and aprepitant/fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Aprepitant is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Administration of a strong CYP3A4 inhibitor increased the aprepitant AUC and mean terminal half-life by approximately 5-fold and 3-fold, respectively.
    Arformoterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Aripiprazole: (Major) Avoid use of aripiprazole with ceritinib if possible due to the risk of QT prolongation. Ceritinib causes concentration-dependent QT prolongation. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole and following overdose. If concurrent use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as ceritinib. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if ceritinib is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of ceritinib for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving ceritinib or patients receiving a combination of ceritinib 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. Adult patients receiving Abilify Maintena who are PMs and receiving ceritinib should have a dose reduction to 200 mg/month IM. Patients receiving a combination of ceritinib and a CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving ceritinib for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and ceritinib for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and ceritinib because the dose of Aristada Initio cannot be modified.
    Arsenic Trioxide: (Major) Avoid coadministration of arsenic trioxide with ceritinib due to the risk of QT interval prolongation; discontinue ceritinib or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently 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. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Ceritinib also causes concentration-dependent prolongation of the QT interval.
    Artemether; Lumefantrine: (Major) Avoid coadministration of ceritinib with artemether due to the risk of QT prolongation; plasma concentrations of artemether may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and periodically monitor electrolytes; also watch for artemether-related adverse reactions. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a strong CYP3A4 inhibitor that causes a concentration-dependent prolongation of the QT interval. Artemether is a CYP3A4 substrate that has also been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased artemether exposure by 2.3-fold. (Major) Avoid coadministration of ceritinib with lumefantrine due to the risk of QT prolongation; plasma concentrations of lumefantrine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and periodically monitor electrolytes; also watch for lumefantrine-related adverse reactions. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a strong CYP3A4 inhibitor that causes a concentration-dependent prolongation of the QT interval. Lumefantrine is a CYP3A4 substrate that has also been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold.
    Asenapine: (Major) Avoid coadministration of asenapine with ceritinib due to the risk of QT prolongation. Asenapine has been associated with QT prolongation. Concentration-dependent QT prolongation has also been reported with ceritinib treatment.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ceritinib 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 ceritinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ceritinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Dihydrocodeine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. If ceritinib 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 strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib with atazanavir due to increased exposure to ceritinib. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After atazanavir is discontinued, resume the dose of ceritinib taken prior to initiating atazanavir. Ceritinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of ceritinib with atazanavir due to increased exposure to ceritinib. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After atazanavir is discontinued, resume the dose of ceritinib taken prior to initiating atazanavir. Ceritinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects. (Major) Avoid coadministration of ceritinib with cobicistat due to increased exposure to ceritinib; cobicistat exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Atenolol: (Major) Avoid coadministration of ceritinib with atenolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; atenolol also causes bradycardia.
    Atenolol; Chlorthalidone: (Major) Avoid coadministration of ceritinib with atenolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; atenolol also causes bradycardia.
    Atomoxetine: (Major) Avoid coadministration of ceritinib with atomoxetine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Prolongation of the QT interval has occurred during therapeutic use of atomoxetine as well as following overdose.
    Atorvastatin: (Major) Consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness) if coadministration of atorvastatin with ceritinib is required, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ceritinib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration of ceritinib with atorvastatin may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin.
    Atorvastatin; Ezetimibe: (Major) Consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness) if coadministration of atorvastatin with ceritinib is required, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ceritinib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration of ceritinib with atorvastatin may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of ceritinib with phenobarbital due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Avanafil: (Major) Do not use avanafil in patients receiving ceritinib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
    Axitinib: (Major) Avoid coadministration of axitinib with ceritinib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ceritinib is discontinued. Axitinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and ceritinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Azithromycin: (Major) Avoid coadministration of ceritinib with azithromycin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Concurrent use of bedaquiline and ceritinib should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure; there is also an increased risk of QT prolongation. Bedaquiline is a CYP3A4 substrate that has been reported to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor associated with concentration-dependent QT prolongation. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) Coadministration of ergotamine and ceritinib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors. (Major) Avoid coadministration of ceritinib with phenobarbital due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Bendroflumethiazide; Nadolol: (Major) Avoid coadministration of ceritinib with nadolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; nadolol also causes bradycardia.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with ceritinib 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 ceritinib 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 ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Betaxolol: (Major) Avoid coadministration of ceritinib with betaxolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; betaxolol also causes bradycardia.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of ceritinib with metronidazole if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of ceritinib with metronidazole if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bisoprolol: (Major) Avoid coadministration of ceritinib with bisoprolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; bisoprolol also causes bradycardia.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of ceritinib with bisoprolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; bisoprolol also causes bradycardia.
    Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ceritinib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
    Bosentan: (Moderate) Use caution if coadministration of ceritinib 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 ceritinib and a strong or moderate CYP2C9 inhibitor is not recommended. Ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Bosentan is a CYP3A4 and CYP2C9 substrate.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and ceritinib; 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 ceritinib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
    Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ceritinib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
    Brexpiprazole: (Major) Reduce the brexpiprazole dose to half the usual dose if coadministered with ceritinib. Administer one quarter of the usual brexpiprazole dose if the patient is also receiving a strong or moderate CYP2D6 inhibitor or is a known poor metabolizer of CYP2D6. If ceritinib is discontinued, adjust the brexpiprazole dosage to its original level. Ceritinib is a strong CYP3A4 inhibitor. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brigatinib: (Major) Avoid coadministration of brigatinib with ceritinib if possible due to increased plasma exposure of brigatinib. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ceritinib, resume the brigatinib dose that was tolerated prior to initiation of ceritinib. Brigatinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Brimonidine; Timolol: (Major) Avoid coadministration of ceritinib with timolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; timolol also causes bradycardia.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with ceritinib ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; ceritinib is a strong inhibitor of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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: (Major) Avoid coadministration of oral budesonide and ceritinib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Formoterol: (Major) Avoid coadministration of oral budesonide and ceritinib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor; lidocaine is metabolized by CYP3A4 and CYP1A2. Concomitant treatment CYP3A4 inhibitors has the potential to increase lidocaine plasma levels by decreasing lidocaine clearance and prolonging the elimination half-life.
    Buprenorphine: (Major) Avoid coadministration of ceritinib with buprenorphine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping ceritinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency; consider increasing buprenorphine dosage until stable drug effects are achieved and monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation.
    Buprenorphine; Naloxone: (Major) Avoid coadministration of ceritinib with buprenorphine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping ceritinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency; consider increasing buprenorphine dosage until stable drug effects are achieved and monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation.
    Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with ceritinib. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering ceritinib with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4. Ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects.
    Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with ceritinib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ceritinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with ceritinib due to the risk of increased cabozantinib exposure. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day); for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 100 mg/day or 100 mg/day to 60 mg/day). Resume the cabozantinib dose that was used prior to initiating treatment with ceritinib 2 to 3 days after discontinuation of ceritinib. Cabozantinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased single-dose cabozantinib exposure by 38%.
    Caffeine; Ergotamine: (Severe) Coadministration of ergotamine and ceritinib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with ceritinib. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A4; ceritinib is a strong inhibitor of CYP3A4.
    Carbamazepine: (Major) Avoid coadministration of ceritinib with carbamazepine due to decreased ceritinib exposure, resulting in decreased efficacy of treatment; carbamazepine exposure may also increase. Ceritinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively. Additionally, ceritinib is a strong CYP3A4 inhibitor and carbamazepine is a CYP3A4 substrate with a narrow therapeutic index.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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.
    Cariprazine: (Major) The dose of cariprazine should be reduced in patients also receiving ceritinib. When ceritinib is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on ceritinib, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. When ceritinib is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. Ceritinib is a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
    Carteolol: (Major) Avoid coadministration of ceritinib with carteolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; carteolol also causes bradycardia.
    Carvedilol: (Major) Avoid coadministration of ceritinib with carvedilol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; carvedilol also causes bradycardia.
    Cevimeline: (Moderate) Monitor for an increase in cevimeline-related adverse reactions if coadministration with ceritinib is necessary. Cevimeline is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration may increase systemic exposure of cevimeline.
    Chloramphenicol: (Major) Avoid coadministration of ceritinib with chloramphenicol due to increased exposure to ceritinib. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After chloramphenicol is discontinued, resume the dose of ceritinib taken prior to initiating chloramphenicol. Ceritinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Chlordiazepoxide: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of chlordiazepoxide with ceritinib is necessary. Chlordiazepoxide is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chlordiazepoxide; Clidinium: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of chlordiazepoxide with ceritinib is necessary. Chlordiazepoxide is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chloroquine: (Major) Avoid coadministration of ceritinib with chloroquine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Concentration-dependent QT prolongation has also occurred with ceritinib treatment.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with ceritinib 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 ceritinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ceritinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Dihydrocodeine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ceritinib 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 ceritinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ceritinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Dihydrocodeine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib with chlorpromazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Chlorthalidone; Clonidine: (Major) Avoid coadministration of ceritinib with clonidine if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; clonidine also causes bradycardia.
    Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with ceritinib. Monitor for an increase in cilostazol-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    Cinacalcet: (Major) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with ceritinib; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of cinacalcet by 127% and 116%, respectively.
    Ciprofloxacin: (Major) Avoid coadministration of ceritinib with ciprofloxacin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsade de pointes, use of cisapride with ceritinib is contraindicated. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Ceritinib also prolongs the QT interval.
    Citalopram: (Major) Coadministration of citalopram with ceritinib is not recommended due to the risk of QT prolongation; citalopram exposure may also be increased. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Citalopram is a CYP3A4 substrate that causes dose-dependent QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that is also associated with concentration-dependent QT prolongation.
    Clarithromycin: (Major) Avoid coadministration of ceritinib with clarithromycin due to the risk of QT prolongation and increased ceritinib exposure. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, further dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After clarithromycin is discontinued, resume the dose of ceritinib taken prior to initiating clarithromycin. Ceritinib is a CYP3A4 substrate that causes concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that is also associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions if coadministration with ceritinib is necessary. Clindamycin is a CYP3A4 substrate and ceritinib is a strong inhibitor of CYP3A4. Plasma concentrations of clindamycin may increase.
    Clofazimine: (Major) Avoid coadministration of ceritinib with clofazimine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs and periodically monitor electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and clomipramine; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 increased sedation and respiratory depression if clonazepam is coadministered with ceritinib; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor and clonazepam is a CYP3A4 substrate.
    Clonidine: (Major) Avoid coadministration of ceritinib with clonidine if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; clonidine also causes bradycardia.
    Clorazepate: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of clorazepate with ceritinib is necessary. Clorazepate is a prodrug whose active metabolite (N-desmethyldiazepam) is a CYP3A4 substrate. Ceritinib is a strong CYP3A4 inhibitor.
    Clozapine: (Major) Avoid coadministration of ceritinib with clozapine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, consider a clozapine dose reduction and monitor for adverse reactions; if ceritinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Clozapine is partially metabolized by CYP3A4 and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use.
    Cobicistat: (Major) Avoid coadministration of ceritinib with cobicistat due to increased exposure to ceritinib; cobicistat exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Cobimetinib: (Major) Avoid coadministration of ceritinib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
    Codeine: (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of ceritinib with promethazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Codeine; Promethazine: (Major) Avoid coadministration of ceritinib with promethazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Moderate) Concomitant use of codeine with ceritinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, 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 ceritinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ceritinib 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. Ceritinib is a strong inhibitor of CYP3A4.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ceritinib in patients with normal renal and hepatic function unless the use of both agents is imperative; If unavoidable, 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 strong CYP3A4 inhibitor like ceritinib 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 once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Colchicine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Colchicine; Probenecid: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ceritinib in patients with normal renal and hepatic function unless the use of both agents is imperative; If unavoidable, 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 strong CYP3A4 inhibitor like ceritinib 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 once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Colchicine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Conivaptan: (Severe) Coadministration of conivaptan and ceritinib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the exposure of oral conivaptan by 11-fold. The effect on the pharmacokinetics of intravenous conivaptan was not evaluated.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of ceritinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and ceritinib if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ceritinib is a strong CYP3A inhibitor.
    Crizotinib: (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.
    Cyclosporine: (Moderate) Monitor serum cyclosporine concentrations when administered concurrently with ceritinib due to potential for elevated cyclosporine concentrations and cyclosporine-related adverse events; cyclosporine dosage adjustment may be necessary. Ceritinib is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    Dabrafenib: (Major) Avoid coadministration of dabrafenib and ceritinib due to increased dabrafenib exposure. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Dabrafenib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%.
    Daclatasvir: (Major) Reduce the daclatasvir dose to 30 mg PO once daily if coadministered with ceritinib due to increased daclatasvir exposure; exposure to ceritinib may also increase. Daclatasvir is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the daclatasvir AUC by 3-fold.
    Dapagliflozin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ceritinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
    Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ceritinib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor.
    Darunavir: (Major) Avoid coadministration of ceritinib with darunavir due to increased exposure to ceritinib; plasma concentrations of darunavir may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After darunavir is discontinued, resume the dose of ceritinib taken prior to initiating darunavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Darunavir; Cobicistat: (Major) Avoid coadministration of ceritinib with cobicistat due to increased exposure to ceritinib; cobicistat exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects. (Major) Avoid coadministration of ceritinib with darunavir due to increased exposure to ceritinib; plasma concentrations of darunavir may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After darunavir is discontinued, resume the dose of ceritinib taken prior to initiating darunavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of ceritinib with cobicistat due to increased exposure to ceritinib; cobicistat exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects. (Major) Avoid coadministration of ceritinib with darunavir due to increased exposure to ceritinib; plasma concentrations of darunavir may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After darunavir is discontinued, resume the dose of ceritinib taken prior to initiating darunavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ceritinib with ritonavir due to increased exposure to ceritinib; plasma concentrations of ritonavir may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After ritonavir is discontinued, resume the dose of ceritinib taken prior to initiating ritonavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with ceritinib is necessary. Paritaprevir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold.
    Dasatinib: (Major) Avoid coadministration of dasatinib and ceritinib due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation. An alternative to ceritinib with no or minimal enzyme inhibition potential is recommended if possible. If concomitant use cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of ceritinib in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue ceritinib or stop dasatinib until ceritinib is discontinued. Allow a washout of approximately 1 week after ceritinib is stopped before increasing the dasatinib dose or reinitiating dasatinib. Periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; ceritinib is a strong CYP3A4 inhibitor that is associated with concentration-dependent QT prolongation. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with ceritinib. 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; ceritinib is a strong inhibitor of CYP3A4. Administration of deflazacort with another strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Major) Avoid coadministration of ceritinib with degarelix if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Androgen deprivation therapy (i.e., degarelix) is also associated with QT prolongation.
    Delavirdine: (Major) Avoid coadministration of ceritinib with delavirdine due to increased exposure to ceritinib; plasma concentrations of delavirdine may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After delavirdine is discontinued, resume the dose of ceritinib taken prior to initiating delavirdine. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Desflurane: (Major) Avoid coadministration of ceritinib with halogenated anesthetics if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and desipramine; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib with deutetrabenazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, for patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing either the deutetrabenazine or ceritinib dosage. Ceritinib causes concentration-dependent QT prolongation. Clinically relevant QTc prolongation may also occur with deutetrabenazine.
    Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of ceritinib with dexamethasone is necessary, due to increased dexamethasone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Consider the use of corticosteroids such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, especially for long-term use. Ceritinib is a strong CYP3A4 inhibitor and dexamethasone is primarily metabolized by CYP3A4. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
    Dexlansoprazole: (Moderate) Monitor for dexlansoprazole-related adverse reactions (e.g., GI effects) if coadministration with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor, while dexlansoprazole is a CYP3A4 substrate. Plasma concentrations of dexlansoprazole may be elevated when administered concurrently with ceritinib.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of ceritinib with promethazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of ceritinib with quinidine if possible due to the risk of QT prolongation; plasma concentrations of quinidine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Quinidine is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Diazepam: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of diazepam with ceritinib is necessary. At low concentrations, diazepam is a CYP2C19 substrate but at high concentrations, CYP3A4 is also involved. Ceritinib is a strong CYP3A4 inhibitor.
    Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with ceritinib is necessary; adjust the dose of diclofenac if needed. Diclofenac is a CYP2C9 substrate and ceritinib is a weak CYP2C9 inhibitor.
    Diclofenac; Misoprostol: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with ceritinib is necessary; adjust the dose of diclofenac if needed. Diclofenac is a CYP2C9 substrate and ceritinib is a weak CYP2C9 inhibitor.
    Digoxin: (Major) Avoid coadministration of ceritinib with digoxin if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; digoxin also causes bradycardia.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ceritinib 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 ceritinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ceritinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Dihydrocodeine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Dihydroergotamine: (Severe) Coadministration of dihydroergotamine with ceritinib is contraindicated due to the potential for elevated dihydroergotamine exposure. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ceritinib is a strong inhibitor of CYP3A4; dihydroergotamine is a CYP3A4 substrate.
    Diltiazem: (Major) Avoid coadministration of ceritinib with diltiazem if possible due to the risk of additive bradycardia; plasma concentrations of diltiazem may also increase. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; diltiazem also causes bradycardia. Additionally, diltiazem is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib with disopyramide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, closely monitor for disopyramide-related adverse reactions. Disopyramide is a CYP3A4 substrate that has been associated with QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when administered with another strong CYP3A4 inhibitor.
    Docetaxel: (Major) Avoid coadministration of docetaxel with ceritinib if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
    Dofetilide: (Major) Avoid coadministration of ceritinib with dofetilide due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Dofetilide is a CYP3A4 substrate that is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that is also associated with concentration-dependent QT prolongation.
    Dolasetron: (Major) Avoid coadministration of ceritinib with dolasetron if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes 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: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with ceritinib is necessary. Dolutegravir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with ceritinib is necessary. Dolutegravir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of ceritinib with rilpivirine if possible due to the risk of QT prolongation; plasma concentrations of rilpivirine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Ceritinib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of rilpivirine by 1.49-fold. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with ceritinib is necessary. Dolutegravir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Donepezil: (Major) Avoid coadministration of ceritinib with donepezil if possible due to the risk of QT prolongation; plasma concentrations of donepezil may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Also, monitor for donepezil-related adverse reactions (e.g., GI or cholinergic effects). Donepezil is a CYP3A4 substrate that has had case reports of QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Donepezil; Memantine: (Major) Avoid coadministration of ceritinib with donepezil if possible due to the risk of QT prolongation; plasma concentrations of donepezil may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Also, monitor for donepezil-related adverse reactions (e.g., GI or cholinergic effects). Donepezil is a CYP3A4 substrate that has had case reports of QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Doravirine: (Minor) Monitor for an increase in doravirine-related adverse reactions if coadministration with ceritinib is necessary; increased doravirine plasma concentrations may occur. Doravirine is a CYP3A4 substrate; ceritinib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Monitor for an increase in doravirine-related adverse reactions if coadministration with ceritinib is necessary; increased doravirine plasma concentrations may occur. Doravirine is a CYP3A4 substrate; ceritinib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Dorzolamide; Timolol: (Major) Avoid coadministration of ceritinib with timolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; timolol also causes bradycardia.
    Doxepin: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and doxepin; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (Moderate) Monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, feeling high, dizziness, somnolence) if coadministration with ceritinib is necessary. Concomitant use may result in elevated plasma concentrations of dronabinol. Ceritinib is a strong CYP3A4 inhibitor and a weak inhibitor of CYP2C9. Dronabinol is a CYP2C9 and 3A4 substrate.
    Dronedarone: (Severe) The concomitant use of dronedarone with ceritinib is contraindicated due to the risk of QT prolongation and torsade de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval; the increase is approximately 10 msec at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 msec at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, such as ceritinib, coadministration of such drugs may result in additive QT prolongation. Additionally, dronedarone is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as ceritinib. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes. Concentration-dependent QT prolongation has been reported with ceritinib. 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.
    Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Dutasteride: (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with ceritinib is necessary. Dutasteride is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
    Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and ceritinib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 like ceritinib are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with ceritinib is necessary. Dutasteride is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
    Duvelisib: (Major) Reduce the duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with ceritinib. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; ceritinib is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as ceritinib.
    Efavirenz: (Major) Avoid coadministration of ceritinib with efavirenz if possible due to the risk of QT prolongation; plasma concentrations of efavirenz may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for an increase in efavirenz-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of ceritinib with efavirenz if possible due to the risk of QT prolongation; plasma concentrations of efavirenz may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for an increase in efavirenz-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ceritinib with efavirenz if possible due to the risk of QT prolongation; plasma concentrations of efavirenz may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for an increase in efavirenz-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and ceritinib for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ceritinib to 6 months. Elagolix is a CYP3A substrate and ceritinib is a strong inhibitor of CYP3A. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
    Elbasvir; Grazoprevir: (Moderate) Monitor for an increase in elbasvir-related adverse reactions if coadministration with ceritinib is necessary. Elbasvir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased elbasvir exposure by 3-fold. (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with ceritinib is necessary. Grazoprevir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold.
    Eletriptan: (Severe) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of ceritinib due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
    Elexacaftor; tezacaftor; ivacaftor: (Major) If ceritinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor when coadministered with ceritinib; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor/tezacaftor/ivacaftor combination tablets twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ceritinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of ceritinib and eliglustat is contraindicated. The coadministration of eliglustat with both ceritinib and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. In other patients, avoid coadministration of ceritinib and eliglustat if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, reduce the dose of eliglustat to 84 mg PO once daily in extensive CYP2D6 metabolizers (EMs). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Eliglustat is a CYP3A and CYP2D6 substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of eliglustat with CYP3A inhibitors such as ceritinib increases 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.
    Eluxadoline: (Moderate) Monitor for an increase in eluxadoline-related adverse reactions including impaired mental or physical abilities if coadministration with ceritinib is necessary. The metabolism of eluxadoline by CYP pathways has not been clearly established, but strong CYP inhibitors such as ceritinib have the potential to increase eluxadoline exposure.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of ceritinib with cobicistat due to increased exposure to ceritinib; cobicistat exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ceritinib with cobicistat due to increased exposure to ceritinib; cobicistat exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of ceritinib with rilpivirine if possible due to the risk of QT prolongation; plasma concentrations of rilpivirine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Ceritinib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of rilpivirine by 1.49-fold.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of ceritinib with rilpivirine if possible due to the risk of QT prolongation; plasma concentrations of rilpivirine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Ceritinib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of rilpivirine by 1.49-fold.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and ceritinib 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 ceritinib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
    Encorafenib: (Major) Avoid coadministration of encorafenib and ceritinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ceritinib; monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ceritinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ceritinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ceritinib is a strong CYP3A4 inhibitor that can also cause concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Enflurane: (Major) Avoid coadministration of ceritinib with halogenated anesthetics if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Entrectinib: (Major) Avoid coadministration of entrectinib with ceritinib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ceritinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ceritinib. Additionally, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for ceritinib if QT prolongation occurs. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ceritinib is a strong CYP3A4 inhibitor that is associated with concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Enzalutamide: (Major) Avoid coadministration of ceritinib with enzalutamide due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Eplerenone: (Severe) Eplerenone is contraindicated for use with ceritinib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Ceritinib is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and ceritinib due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If ceritinib is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
    Ergotamine: (Severe) Coadministration of ergotamine and ceritinib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors.
    Eribulin: (Major) Avoid coadministration of ceritinib with eribulin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Eribulin is also associated with QT prolongation.
    Erlotinib: (Major) Avoid coadministration of erlotinib with ceritinib if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Erythromycin: (Major) Avoid coadministration of ceritinib with erythromycin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Erythromycin is associated with QT prolongation and torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of ceritinib with erythromycin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Erythromycin is associated with QT prolongation and torsade de pointes (TdP).
    Escitalopram: (Major) Avoid coadministration of ceritinib with escitalopram if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes 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 ceritinib with esmolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; esmolol also causes bradycardia.
    Estazolam: (Moderate) Monitor for estazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and estazolam is primarily metabolized by CYP3A4. In vivo drug-drug interaction studies were not conducted between estazolam and inhibitors of CYP3A.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Use caution if coadministration of ceritinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
    Eszopiclone: (Major) The total dose of eszopiclone should not exceed 2 mg when administered with ceritinib. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased eszopiclone exposure by 2.2-fold.
    Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Desogestrel: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norgestimate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with ceritinib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and ceritinib is a strong CYP3A4 inhibitor.
    Etoposide, VP-16: (Moderate) Monitor for an increase in etoposide-related adverse reactions if coadministration with ceritinib is necessary. Etoposide is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if coadministration with ceritinib is necessary. Etravirine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased etravirine exposure by 1.42-fold.
    Everolimus: (Major) Avoid coadministration of everolimus with ceritinib due to increased exposure to everolimus resulting in an increase of everolimus-related adverse reactions. Re-assess everolimus trough concentrations 2 weeks after discontinuation of ceritinib for indications where therapeutic drug monitoring is necessary. Everolimus is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased everolimus exposure by 15-fold.
    Ezetimibe; Simvastatin: (Severe) Concurrent use of simvastatin and ceritinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Ezogabine: (Major) Avoid coadministration of ceritinib with ezogabine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Ezogabine has also been associated with QT prolongation.
    Fedratinib: (Major) Avoid coadministration of fedratinib with ceritinib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ceritinib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Felodipine: (Moderate) Concurrent use of felodipine and ceritinib 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 ceritinib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-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 ceritinib is necessary. If ceritinib 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 CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib with fingolimod if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Initiation of other drugs during the 2 months after fingolimod discontinuation warrants the same considerations needed for concomitant administration because fingolimod remains in the blood and has pharmacodynamic effects for up to 2 months after the last dose. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib with flecainide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Flibanserin: (Severe) The concomitant use of flibanserin and strong CYP3A4 inhibitors such as ceritinib is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of ceritinib, start flibanserin at least 2 weeks after the last dose of ceritinib. If initiating ceritinib following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating ceritinib therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ceritinib, is contraindicated. Fluconazole has been associated with QT prolongation and concentration-dependent QT prolongation has been reported with ceritinib.
    Fluoxetine: (Major) Avoid coadministration of ceritinib with fluoxetine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of ceritinib with fluoxetine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine. (Major) Avoid coadministration of ceritinib with olanzapine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as ceritinib.
    Flurazepam: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of flurazepam with ceritinib is necessary. Flurazepam is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and ceritinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Fluticasone; Salmeterol: (Major) Coadministration of inhaled fluticasone propionate and ceritinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ceritinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ceritinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Fluvoxamine: (Major) Avoid coadministration of ceritinib with fluvoxamine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during postmarketing experience with fluvoxamine.
    Formoterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Formoterol; Mometasone: (Moderate) Coadministration of mometasone with ceritinib may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; ceritinib is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Fosamprenavir: (Major) Avoid coadministration of ceritinib with fosamprenavir due to increased exposure to ceritinib; plasma concentrations of fosamprenavir may also be increased. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. After fosamprenavir is discontinued, resume the dose of ceritinib taken prior to initiating fosamprenavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Foscarnet: (Major) Avoid coadministration of foscarnet with ceritinib due to the risk of QT prolongation. Ceritinib causes concentration-dependent prolongation of the QT interval. If coadministration cannot be avoided, conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of ceritinib with fosphenytoin due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Fostamatinib: (Moderate) Monitor for an increase in fostamatinib-related adverse reactions if coadministration with ceritinib is necessary. Fostamatinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to R406 (the major active metabolite of fostamatinib) by 102%.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ceritinib is necessary. Gefitinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Gemifloxacin: (Major) Avoid coadministration of ceritinib with gemifloxacin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Gemifloxacin may prolong the QT interval in some patients; the maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration. 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 ceritinib with gemtuzumab if possible due to the risk of QT prolongation. If concomitant use is unavoidable, obtain an ECG and serum electrolytes prior to starting concomitant therapy and periodically monitor ECGs and electrolytes during therapy; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes 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) Consider an alternative to ceritinib during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, monitor for gilteritinib-related adverse reactions as well as monitoring periodic ECGs and serum electrolytes. Interrupt therapy, dose reduce, or discontinue treatment if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. In addition, both drugs have been associated with QT prolongation.
    Glasdegib: (Major) Consider an alternative to ceritinib during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended, as well as monitoring electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Glasdegib is a CYP3A4 substrate that causes QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Glyburide: (Moderate) Monitor for glyburide-related adverse reactions including hypoglycemia if coadministered with ceritinib; glyburide exposure may increase. Ceritinib is a weak CYP2C9 inhibitor and glyburide is primarily metabolized by CYP2C9.
    Glyburide; Metformin: (Moderate) Monitor for glyburide-related adverse reactions including hypoglycemia if coadministered with ceritinib; glyburide exposure may increase. Ceritinib is a weak CYP2C9 inhibitor and glyburide is primarily metabolized by CYP2C9.
    Glycopyrrolate; Formoterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Goserelin: (Major) Avoid coadministration of ceritinib with goserelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
    Granisetron: (Major) Avoid coadministration of ceritinib with granisetron if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Granisetron has also been associated with QT prolongation.
    Grapefruit juice: (Major) Patients should not consume grapefruit and grapefruit juice during ceritinib therapy. Avoid coadministration of ceritinib with grapefruit or grapefruit juice due to increased ceritinib exposure. Ceritinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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) If coadministration of ceritinib with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If ceritinib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Ceritinib may significantly increase guanfacine plasma concentrations.
    Halogenated Anesthetics: (Major) Avoid coadministration of ceritinib with halogenated anesthetics if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of ceritinib with haloperidol if possible due to the risk of QT prolongation; plasma concentrations of haloperidol may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for haloperidol-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Haloperidol is a CYP3A4 substrate that has caused QT prolongation and torsade de pointes (TdP) during treatment; excessive doses (particularly in the overdose setting) or IV administration 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 ceritinib with halogenated anesthetics if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Histrelin: (Major) Avoid coadministration of ceritinib with histrelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib with metoprolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; metoprolol also causes bradycardia.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Avoid coadministration of ceritinib with propranolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; propranolol also causes bradycardia.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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) Hydroxychloroquine prolongs the QT interval and should not be administered with other drugs known to prolong the QT interval, such as ceritinib which causes concentration-dependent QT prolongation.
    Hydroxyzine: (Major) Avoid coadministration of ceritinib with hydroxyzine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Postmarketing data indicate that hydroxyzine also causes QT prolongation and torsade de pointes (TdP).
    Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and ceritinib, as ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. If ceritinib 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 strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib with ibutilide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid coadministration of ceritinib with idelalisib due to increased exposure to ceritinib; idelalisib exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After idelalisib is discontinued, resume the dose of ceritinib taken prior to initiating idelalisib. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with a strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%. Coadministration with a strong CYP3A inhibitor increased the AUC of idelalisib by 1.8-fold.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ceritinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ceritinib is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Major) Avoid coadministration of iloperidone with ceritinib due to the risk of QT prolongation; plasma concentrations of iloperidone may also increase. Iloperidone is a CYP3A4 substrate that has been associated with QT prolongation. Concentration-dependent QT prolongation has also been reported with ceritinib, a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to iloperidone and its metabolites P88 and P95 by 57%, 55%, and 35%, respectively.
    Imatinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with ceritinib is necessary. Imatinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
    Imipramine: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and imipramine; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Indacaterol; Glycopyrrolate: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Indinavir: (Major) Avoid coadministration of ceritinib with indinavir due to increased exposure to ceritinib; indinavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After indinavir is discontinued, resume the dose of ceritinib taken prior to initiating indinavir. Ceritinib is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Indinavir is a sensitive CYP3A4 substrate, as well as a strong CYP3A4 inhibitor.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with ceritinib 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 if QT prolongation occurs. Inotuzumab has been associated with QT interval prolongation. Concentration-dependent QT prolongation has been reported with ceritinib.
    Irinotecan Liposomal: (Major) Discontinue ceritinib at least 1 week prior to starting irinotecan therapy; do not administer ceritinib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
    Irinotecan: (Major) Discontinue ceritinib at least 1 week prior to starting irinotecan therapy; do not administer ceritinib with irinotecan unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to both irinotecan and SN-38.
    Isavuconazonium: (Severe) Coadministration of isavuconazonium with ceritinib is contraindicated due to the risk of increased isavuconazole exposure. Isavuconazole is a sensitive substrate of CYP3A4 and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased isavuconazole exposure by 422%.
    Isoflurane: (Major) Avoid coadministration of ceritinib with halogenated anesthetics if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ceritinib with rifampin due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ceritinib with rifampin due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Isradipine: (Moderate) Monitor for hypotension if coadministration of ceritinib with isradipine is necessary. Ceritinib is a strong CYP3A4 inhibitor and isradipine is metabolized by CYP3A4. Concomitant use may increase isradipine exposure, increasing the risk for isradipine-related adverse reactions.
    Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ceritinib as istradefylline exposure and adverse effects may increase. Ceritinib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
    Itraconazole: (Major) Avoid use of ceritinib during and for 2 weeks after itraconazole due to increased exposure to ceritinib; itraconazole exposure may also increase. If coadministration cannot be avoided, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After itraconazole is discontinued, resume the dose of ceritinib taken prior to initiating itraconazole. Itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis, the decline in plasma concentrations may be more gradual. Ceritinib is a CYP3A4 substrate and inhibitor that causes concentration-dependent prolongation of the QT interval. Itraconazole is a CYP3A4 substrate as well as a strong CYP3A4 inhibitor, and is also associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%.
    Ivabradine: (Severe) Coadministration of ceritinib with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Ivacaftor: (Major) If ceritinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with ceritinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ceritinib is discontinued, wait at least 5 half-lives of ceritinib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
    Ixabepilone: (Major) Avoid coadministration of ceritinib with ixabepilone if possible due to increased ixabepilone exposure. If concomitant use is unavoidable, consider reducing the dose of ixabepilone to 20 mg/m2. If ceritinib is discontinued, resume the original dose of ixabepilone after a washout period of approximately 1 week. Ixabepilone is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ixabepilone exposure by 79%.
    Ketoconazole: (Major) Avoid coadministration of ceritinib with ketoconazole due to increased exposure to ceritinib; additive QT prolongation and increased ketoconazole exposure may also occur. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with ketoconazole increased ceritinib exposure by 2.9-fold in healthy subjects. Concentration-dependent QT prolongation has been reported with ceritinib therapy. Ketoconazole is also associated with QT prolongation.
    Labetalol: (Major) Avoid coadministration of ceritinib with labetolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; labetolol also causes bradycardia.
    Lapatinib: (Major) Avoid coadministration of lapatinib with ceritinib due to increased plasma concentrations of lapatinib and the risk of QT prolongation. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If ceritinib is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Ceritinib is a strong CYP3A4 inhibitor that also causes concentration-dependent QT prolongation. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with ceritinib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ceritinib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ceritinib. Larotrectinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Lefamulin: (Major) Avoid coadministration of lefamulin with ceritinib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ceritinib is a strong CYP3A4 that can cause concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with ceritinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ceritinib causes concentration-dependent QT prolongation.
    Letermovir: (Moderate) Avoid coadministration of ceritinib with letermovir if the patient is also taking cyclosporine. If this combination (ceritinib/letermovir/cyclosporine) is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. No dose adjustment or special precautions are necessary if ceritinib and letermovir are coadministered without cyclosporine. Ceritinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor, but the combined effect when given with cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Leuprolide: (Major) Avoid coadministration of ceritinib with leuprolide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of ceritinib with leuprolide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Levalbuterol: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Levobunolol: (Major) Avoid coadministration of ceritinib with levobunolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; levobunolol also causes bradycardia.
    Levofloxacin: (Major) Avoid coadministration of ceritinib with levofloxacin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Levofloxacin has also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TDP) has been reported during postmarketing surveillance of levofloxacin.
    Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with ceritinib is necessary. Levomilnacipran is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased levomilnacipran exposure by about 50%.
    Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor; lidocaine is metabolized by CYP3A4 and CYP1A2. Concomitant treatment CYP3A4 inhibitors has the potential to increase lidocaine plasma levels by decreasing lidocaine clearance and prolonging the elimination half-life.
    Lithium: (Major) Avoid coadministration of ceritinib with lithium if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Lithium is also associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of ceritinib with lofexidine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Lofexidine prolongs the QT interval. Ceritinib also causes concentration-dependent prolongation of the QT interval.
    Lomitapide: (Severe) Concomitant use of ceritinib and lomitapide is contraindicated; if treatment with ceritinib is unavoidable, lomitapide should be stopped during treatment. Ceritinib is a strong CYP3A4 inhibitor and lomitapide is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lomitapide exposure approximately 27-fold.
    Long-acting beta-agonists: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Loperamide: (Major) Avoid coadministration of ceritinib with loperamide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for an increase in loperamide-related adverse reactions, including cardiac effects. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. 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. Coadministration with another strong CYP3A4 inhibitor increased loperamide exposure by 2.9- to 3.8-fold.
    Loperamide; Simethicone: (Major) Avoid coadministration of ceritinib with loperamide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for an increase in loperamide-related adverse reactions, including cardiac effects. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. 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. Coadministration with another strong CYP3A4 inhibitor increased loperamide exposure by 2.9- to 3.8-fold.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of ceritinib with lopinavir due to increased exposure to ceritinib; additive QT prolongation and increased lopinavir exposure may also occur. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After lopinavir is discontinued, resume the dose of ceritinib taken prior to initiating lopinavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects. Lopinavir; ritonavir is associated with QT prolongation. Concentration-dependent QT prolongation also occurred with ceritinib therapy. (Major) Avoid coadministration of ceritinib with ritonavir due to increased exposure to ceritinib; plasma concentrations of ritonavir may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After ritonavir is discontinued, resume the dose of ceritinib taken prior to initiating ritonavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Lorlatinib: (Major) Avoid coadministration of lorlatinib with ceritinib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib. If concomitant use is unavoidable, decrease the starting dose of lorlatinib from 100 mg PO once daily to 75 mg PO once daily. In patients who have already had a dose reduction to 75 mg PO once daily due to adverse reactions, reduce the dose of lorlatinib to 50 mg PO once daily. If ceritinib is discontinued, increase the dose of lorlatinib after 3 plasma half-lives of ceritinib to the dose that was used before starting ceritinib. Lorlatinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of lorlatinib by 42% and 24%, respectively.
    Lovastatin: (Severe) Coadministration of lovastatin and ceritinib is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold.
    Lovastatin; Niacin: (Severe) Coadministration of lovastatin and ceritinib is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ceritinib with lumacaftor; ivacaftor due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively. (Major) If ceritinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ceritinib with lumacaftor; ivacaftor due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Lurasidone: (Severe) Coadministration of lurasidone with ceritinib is contraindicated due to increased plasma concentrations of lurasidone. Lurasidone is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lurasidone exposure by 9-fold.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ceritinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of ceritinib prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Concentration-dependent QT prolongation has been reported with ceritinib.
    Macitentan: (Major) Avoid coadministration of macitentan with ceritinib due to the risk of increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor approximately doubled macitentan exposure.
    Maprotiline: (Major) Avoid coadministration of ceritinib with maprotiline if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Maprotiline has 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.
    Maraviroc: (Major) Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors such as ceritinib; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCL less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with ceritinib (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily. The AUC of maraviroc was increased by up to approximately 10-fold in the presence of strong CYP3A4 inhibitors.
    Medroxyprogesterone: (Moderate) Use caution if coadministration of ceritinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
    Mefloquine: (Major) Avoid coadministration of ceritinib with mefloquine if possible due to the risk of QT prolongation; plasma concentrations of mefloquine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. 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. Ceritinib is a strong CYP3A4 inhibitor that has been reported to cause concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased mefloquine exposure by 79%.
    Meperidine; Promethazine: (Major) Avoid coadministration of ceritinib with promethazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Mephobarbital: (Major) Avoid coadministration of ceritinib with mephobarbital due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate; mephobarbital is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Metaproterenol: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with ceritinib is necessary. Repaglinide is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
    Metformin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ceritinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
    Methadone: (Major) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary; carefully assess the benefits of treatment with the risks of therapy, including QT prolongation. Periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. If ceritinib 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, and coadministration with strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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. Additionally, concentration-dependent QT prolongation has been reported with ceritinib therapy. Methadone is 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.
    Methylprednisolone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of ceritinib with methylprednisolone is necessary, due to increased methylprednisolone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Ceritinib is a strong CYP3A4 inhibitor and methylprednisolone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
    Metoprolol: (Major) Avoid coadministration of ceritinib with metoprolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; metoprolol also causes bradycardia.
    Metronidazole: (Major) Avoid coadministration of ceritinib with metronidazole if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midazolam: (Moderate) Monitor for increased sedation and respiratory depression if coadministration of midazolam with ceritinib is necessary. Midazolam is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Daily administration of ceritinib increased the AUC and Cmax of single-dose midazolam by 5.4-fold and 1.8-fold, respectively.
    Midostaurin: (Major) Consider alternative therapies to ceritinib if a patient is receiving midostaurin therapy due to the potential for increased plasma concentrations of midostaurin resulting in toxicity; QT prolongation may also occur. If treatment with ceritinib is necessary, monitor for an increase in midostaurin-related adverse reactions, especially during the first week of consecutive midostaurin administration in patients with advanced systemic mastocytosis, and during the first week of midostaurin administration in each cycle of chemotherapy for patients with acute myelogenous leukemia (AML). Periodically 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. Midostaurin is a sensitive CYP3A4 substrate that has had reports of QT prolongation in clinical trials. Ceritinib is a strong CYP3A4 inhibitor that has had reports of concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of midostaurin by 10.4-fold and of CGP62221 by 3.5-fold. Coadministration with a different strong CYP3A4 inhibitor increased the day 28 Cmin of midostaurin by 2.1-fold and CGP6221 by 1.2-fold.
    Mifepristone: (Major) Caution is advised when administering ceritinib with mifepristone for pregnancy termination due to increased exposure to mifepristone; QT prolongation may also occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with ceritinib should be done only when necessary, and in such cases the dose of mifepristone should be limited to 600 mg per day. In a patient already receiving ceritinib, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with ceritinib is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with ceritinib is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with ceritinib is initiated in a patient already receiving mifepristone 900 mg or 1200 mg, reduce the mifepristone dose to 600 mg. Periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. Mifepristone is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Both drugs have been associated with dose- or concentration-dependent QT prolongation.
    Mirtazapine: (Major) Avoid coadministration of ceritinib with mirtazapine if possible due to the risk of QT prolongation; plasma concentrations of mirtazapine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that is also associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
    Mitotane: (Major) Avoid coadministration of ceritinib with mitotane due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Modafinil: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ceritinib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A4 inhibitors such as ceritinib could increase plasma concentrations of modafinil.
    Mometasone: (Moderate) Coadministration of mometasone with ceritinib may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; ceritinib is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Moxifloxacin: (Major) Avoid coadministration of ceritinib with moxifloxacin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Quinolones have also been associated with a risk of QT prolongation. Although extremely rare, torsade de pointes (TdP) has been reported during postmarketing experience with moxifloxacin; these reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nadolol: (Major) Avoid coadministration of ceritinib with nadolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; nadolol also causes bradycardia.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with ceritinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor.
    Naloxegol: (Severe) Concomitant use of naloxegol with ceritinib is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ceritinib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of albumin-bound paclitaxel with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and paclitaxel is metabolized by CYP3A4. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    Nateglinide: (Moderate) More frequent monitoring of blood glucose may be necessary during coadministration of nateglinide and ceritinib due to the potential for increased nateglinide exposure. A nateglinide dose reduction may be necessary. Ceritinib is a weak CYP2C9 inhibitor and nateglinide is primarily metabolized by CYP2C9.
    Nebivolol: (Major) Avoid coadministration of ceritinib with nebivolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; nebivolol also causes bradycardia.
    Nebivolol; Valsartan: (Major) Avoid coadministration of ceritinib with nebivolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; nebivolol also causes bradycardia.
    Nefazodone: (Major) Avoid coadministration of ceritinib with nefazodone due to increased exposure to ceritinib; plasma concentrations of nefazodone may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After nefazodone is discontinued, resume the dose of ceritinib taken prior to initiating nefazodone. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%.
    Nelfinavir: (Major) Avoid coadministration of ceritinib with nelfinavir due to increased exposure to ceritinib; nelfinavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After nelfinavir is discontinued, resume the dose of ceritinib taken prior to initiating nelfinavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Neratinib: (Major) Avoid concomitant use of ceritinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 481%.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for netupitant-related adverse reactions if coadministration with ceritinib is necessary; however, a dosage adjustment is not necessary. Ceritinib is a strong CYP3A4 inhibitor and netupitant is primarily metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased the mean Cmax and AUC of netupitant by 25% and 140%, respectively.
    Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with ceritinib is necessary. Nevirapine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
    Niacin; Simvastatin: (Severe) Concurrent use of simvastatin and ceritinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Nifedipine: (Moderate) Monitor blood pressure if coadministration of nifedipine with ceritinib is necessary; consider decreasing the dose of nifedipine if appropriate. Nifedipine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Concomitant use may increase nifedipine exposure.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and ceritinib due to increased plasma concentrations of nilotinib which may result in QT prolongation. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. Periodically monitor electrolytes as well. If ceritinib is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and ceritinib is a strong inhibitor of CYP3A4. Concentration-dependent QT prolongation has been reported with ceritinib therapy. Sudden death and QT interval prolongation have occurred in patients who received nilotinib treatment.
    Nimodipine: (Major) Avoid coadministration of nimodipine with ceritinib due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with ceritinib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Nortriptyline: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and nortriptyline; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib with octreotide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Ofloxacin: (Major) Avoid coadministration of ceritinib with ofloxacin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin; these reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Avoid coadministration of ceritinib with olanzapine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib 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 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Olodaterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ceritinib with ritonavir due to increased exposure to ceritinib; plasma concentrations of ritonavir may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After ritonavir is discontinued, resume the dose of ceritinib taken prior to initiating ritonavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with ceritinib is necessary. Paritaprevir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold.
    Ondansetron: (Major) Avoid coadministration of ceritinib with ondansetron if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Both drugs have been associated with dose- or concentration-dependent QT prolongation; there have also been postmarketing reports of torsade de pointes (TdP) with ondansetron therapy.
    Osimertinib: (Major) Avoid coadministration of ceritinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in ceritinib-related adverse reactions, 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, and has also been reported with ceritinib. Additionally, ceritinib is a substrate of P-glycoprotein (P-gp) and osimertinib is a P-gp inhibitor.
    Ospemifene: (Major) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ceritinib is necessary. Ospemifene is a CYP3A4 and CYP2C9 substrate. Ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold. Coadministration with drugs known to inhibit both CYP3A4 and CYP2C9 may increase the risk of ospemifene-related adverse reactions.
    Oxaliplatin: (Major) Avoid coadministration of ceritinib with oxaliplatin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval; QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with ceritinib is necessary. Oxybutynin is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. If ceritinib 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 strong CYP3A4 inhibitors like ceritinib 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 ceritinib 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 ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and paclitaxel is metabolized by CYP3A4. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    Palbociclib: (Major) Avoid coadministration of palbociclib with ceritinib if possible due to the risk of increased palbociclib exposure. If concomitant use is unavoidable, decrease the dose of palbociclib to 75 mg once daily; the original dose of palbociclib may be resumed after 3 to 5 half-lives of the discontinuation of ceritinib. Palbociclib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased palbociclib exposure by 87%.
    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 paliperidone with ceritinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor electrolytes for QT prolongation and monitor electrolytes; close monitoring is essential if the patient has known risk factors for cardiac disease or arrhythmia. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Concentration-dependent QT prolongation has been reported with ceritinib therapy.
    Panobinostat: (Major) Coadministration of panobinostat and ceritinib is not recommended due to the potential for QT prolongation; increased panobinostat exposure is also possible. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Panobinostat is primarily metabolized by CYP3A4 and is also associated with QT prolongation. Coadministration with a strong CYP3A4 inhibitor increased the Cmax and AUC of panobinostat by 62% and 73%, respectively.
    Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and ceritinib, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Ceritinib is a strong CYP3A4 inhibitor and paricalcitol is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor approximately doubled the exposure of paricalcitol.
    Pasireotide: (Major) Avoid coadministration of ceritinib with pasireotide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Pasireotide is also associated with QT prolongation; coadministration may have additive effects.
    Pazopanib: (Major) Avoid coadministration of pazopanib and ceritinib due to the potential for increased pazopanib exposure; QT prolongation may also occur. If concurrent use is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Closely monitor ECGs for QT prolongation; also monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Pazopanib is a CYP3A4 substrate that has been reported to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor that has had reports of concentration-dependent QT prolongation. Concurrent use of another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively.
    Penbutolol: (Major) Avoid coadministration of ceritinib with penbutolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; penbutolol also causes bradycardia.
    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 ceritinib with systemic pentamidine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Systemic pentamidine has been associated with QT prolongation.
    Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong 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%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Perphenazine: (Minor) Perphenazine is 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 such as ceritinib.
    Perphenazine; Amitriptyline: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and amitriptyline; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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) Perphenazine is 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 such as ceritinib.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with ceritinib as concurrent use may increase pexidartinib exposure. If concurrent use cannot be avoided, reduce the dose of pexidartinib. If ceritinib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of ceritinib. Dose adjustments are as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. Pexidartinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased pexidartinib exposure by 70%.
    Phenobarbital: (Major) Avoid coadministration of ceritinib with phenobarbital due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of ceritinib with promethazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of ceritinib with phenytoin due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Pimavanserin: (Major) Pimavanserin should generally be avoided in patients receiving ceritinib due to the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, and loss of balance or coordination. 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. Pimavanserin is a CYP3A4 substrate that may cause QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Pimozide: (Severe) Because of the potential for torsade de pointes, coadministration of pimozide with ceritinib is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ceritinib also prolongs the QT interval.
    Pindolol: (Major) Avoid coadministration of ceritinib with pindolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; pindolol also causes bradycardia.
    Pirbuterol: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Pitolisant: (Major) Avoid coadministration of pitolisant with ceritinib as concurrent use may increase the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Pitolisant also prolongs the QT interval.
    Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ceritinib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ceritinib is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
    Ponatinib: (Major) Avoid coadministration of ponatinib and ceritinib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to 30 mg PO once daily. Ponatinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Posaconazole: (Severe) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ceritinib, is contraindicated. Posaconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP). Ceritinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation.
    Prednisolone: (Minor) Monitor for steroid-related adverse reactions if coadministration of ceritinib with prednisolone is necessary, due to increased prednisolone exposure. Ceritinib is a strong CYP3A4 inhibitor and prednisolone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects; however, plasma concentrations of prednisolone are less affected by strong CYP3A4 inhibitors, especially for long-term use.
    Prednisone: (Minor) Monitor for steroid-related adverse reactions if coadministration of ceritinib with prednisone is necessary, due to increased prednisone exposure. Ceritinib is a strong CYP3A4 inhibitor and prednisolone, the active metabolite of prednisone, is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects; however, plasma concentrations of prednisolone are less affected by strong CYP3A4 inhibitors, especially for long-term use.
    Primaquine: (Major) Avoid coadministration of ceritinib with primaquine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Primaquine is also associated with QT prolongation.
    Primidone: (Major) Avoid coadministration of ceritinib with primidone due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Procainamide: (Major) Avoid coadministration of ceritinib with procainamide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Minor) Prochlorperazine is 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 such as ceritinib.
    Promethazine: (Major) Avoid coadministration of ceritinib with promethazine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of ceritinib with propafenone if possible due to the risk of QT prolongation; plasma concentrations of propafenone may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Avoid coadministration altogether if the patient either has CYP2D6 deficiency or is taking a concomitant CYP2D6 inhibitor, as the risk of proarrhythmia and other adverse events is increased. Propafenone is a CYP2D6 and CYP3A4 substrate as well as a Class IC antiarrhythmic which increases the QT interval, largely due to prolongation of the QRS interval. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Propranolol: (Major) Avoid coadministration of ceritinib with propranolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; propranolol also causes bradycardia.
    Protriptyline: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and protriptyline; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib is necessary; reduce the dose of quazepam if clinically appropriate. Quazepam is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Quetiapine: (Major) Avoid coadministration of ceritinib with quetiapine due to an increased risk for QT prolongation. Systemic exposure of quetiapine may also be increased resulting in increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that quetiapine, a sensitive CYP3A4 substrate, may also be associated with a significant prolongation of the QTc interval in rare instances. Coadministration with another strong CYP3A4 inhibitor significantly increased quetiapine exposure; the manufacturer recommends a large dose reduction when coadministered with strong CYP3A4 inhibitors that do not cause QT prolongation.
    Quinidine: (Major) Avoid coadministration of ceritinib with quinidine if possible due to the risk of QT prolongation; plasma concentrations of quinidine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Quinidine is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Quinine: (Major) Avoid coadministration of quinine with ceritinib due to the risk of QT prolongation; plasma concentrations of quinine may also increase. Quinine is a CYP3A4 substrate that is associated with QT prolongation and rare cases of torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the mean AUC of quinine by 45%.
    Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with ceritinib is necessary. Ramelteon is a CYP3A4 and CYP2C9 substrate. Ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
    Ranolazine: (Severe) Coadministration of ranolazine with ceritinib is contraindicated due to increased plasma concentrations of ranolazine; QT prolongation may also occur. Ranolazine is a CYP3A4 substrate that is associated with dose- and plasma concentration-dependent increases in the QTc interval. Ceritinib is a strong CYP3A4 inhibitor that also causes concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased ranolazine exposure by 220%.
    Regorafenib: (Major) Avoid coadministration of ceritinib with regorafenib due to increased plasma concentrations of regorafenib and decreased exposure to the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with ceritinib is necessary. Repaglinide is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
    Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as ceritinib, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
    Ribociclib: (Major) Avoid coadministration of ceritinib with ribociclib due to the risk of QT prolongation and increased ribociclib exposure; plasma concentrations of ceritinib may also increase. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors that are also associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ceritinib with ribociclib due to the risk of QT prolongation and increased ribociclib exposure; plasma concentrations of ceritinib may also increase. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors that are also associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
    Rifabutin: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with ceritinib is necessary; a dosage adjustment may be necessary. Ceritinib is a strong CYP3A4 inhibitor and rifabutin is primarily metabolized by CYP3A4. Concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin.
    Rifampin: (Major) Avoid coadministration of ceritinib with rifampin due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Rilpivirine: (Major) Avoid coadministration of ceritinib with rilpivirine if possible due to the risk of QT prolongation; plasma concentrations of rilpivirine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Ceritinib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of rilpivirine by 1.49-fold.
    Risperidone: (Major) Avoid coadministration of ceritinib with risperidone if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Reports of QT prolongation and torsade de pointes (TdP) during risperidone therapy are also noted by the manufacturer, primarily in the overdose setting.
    Ritonavir: (Major) Avoid coadministration of ceritinib with ritonavir due to increased exposure to ceritinib; plasma concentrations of ritonavir may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After ritonavir is discontinued, resume the dose of ceritinib taken prior to initiating ritonavir. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Roflumilast: (Moderate) Carefully weigh the risks of increased roflumilast exposure against the benefits of therapy if coadministration with ceritinib is necessary; monitor for roflumilast-related adverse reactions. Roflumilast is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Romidepsin: (Major) Avoid coadministration of ceritinib with romidepsin if possible due to the risk of QT prolongation; plasma concentrations of romidepsin may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for romidepsin-related adverse reactions and follow dose modifications for toxicity during initial administration. Romidepsin is a CYP3A4 substrate that has been reported to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
    Ruxolitinib: (Major) Reduce the ruxolitinib dosage during coadministration with ceritinib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur; no dose adjustments are necessary for patients with graft-versus-host disease. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ceritinib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor.
    Salmeterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Saquinavir: (Severe) Coadministration of saquinavir with ceritinib is contraindicated due to the risk of QT prolongation; increased exposure to both drugs is also possible. Ceritinib is a CYP3A4 substrate and a strong CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Saquinavir is a sensitive CYP3A4 substrate, as well as a strong CYP3A4 inhibitor. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
    Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ceritinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with ceritinib is necessary. Ceritinib is a strong CYP3A4 inhibitor and ethinyl estradiol is a CYP3A4 substrate.
    Sertraline: (Major) Avoid coadministration of ceritinib with sertraline if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. QTc prolongation and torsade de pointes (TdP) have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Avoid coadministration of ceritinib with halogenated anesthetics if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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: (Major) Coadministration with ceritinib is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving ceritinib. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ceritinib is a strong CYP3A4 inhibitor and sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Silodosin: (Severe) Concurrent use of silodosin and ceritinib is contraindicated due to increased plasma concentrations of silodosin resulting in an increase of treatment-related adverse reactions. Silodosin is extensively metabolized by CYP3A4 and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased silodosin exposure by 2.9-fold to 3.2-fold.
    Simeprevir: (Major) Coadministration of simeprevir with ceritinib is not recommended due to increased plasma concentrations of simeprevir which increase the risk for treatment-related adverse reactions. Simeprevir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
    Simvastatin: (Severe) Concurrent use of simvastatin and ceritinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Simvastatin; Sitagliptin: (Severe) Concurrent use of simvastatin and ceritinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving ceritinib 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. Ceritinib causes concentration-dependent prolongation of the QT interval. Additionally, concomitant use of siponimod and ceritinib 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; ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sirolimus: (Major) Avoid coadministration of sirolimus with ceritinib if possible due to increased plasma concentrations of sirolimus resulting in treatment-related adverse reactions. Sirolimus is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Solifenacin: (Major) Avoid coadministration of ceritinib with solifenacin if possible due to the risk of QT prolongation; plasma concentrations of solifenacin may also increase. If concomitant use is unavoidable, do not administer a daily dose of solifenacin greater than 5 mg. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Solifenacin is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Both drugs have been associated with dose- or concentration-dependent QT prolongation, and torsade de pointes (TdP) was reported in postmarketing experience with solifenacin although causality was not determined. Coadministration with another strong CYP3A4 inhibitor increased the mean Cmax and AUC of solifenacin by 1.5- and 2.7-fold, respectively.
    Sonidegib: (Major) Avoid coadministration of sonidegib with ceritinib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
    Sorafenib: (Major) Avoid coadministration of ceritinib with sorafenib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs and electrolytes; correct any electrolyte abnormalities. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Avoid coadministration of ceritinib with sotalol if possible due to the risk of additive bradycardia; QT prolongation may also occur. If unavoidable, monitor heart rate and blood pressure regularly; periodically monitor electrolytes and ECGs. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation or bradycardia occurs. Ceritinib causes concentration-dependent prolongation of the QT interval and bradycardia. Sotalol is also associated with bradycardia, 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 ceritinib with St. John's Wort due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if ceritinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. If ceritinib 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 ceritinib is a strong CYP3A4 inhibitor. Coadministration 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 ceritinib 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 ceritinib with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, consider reducing the dose of sunitinib in 12.5 mg decrements based on individual safety and tolerability to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily. In the adjuvant RCC study, the minimum dose administered was 37.5 mg. Periodically 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. Sunitinib is a CYP3A4 substrate that can prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
    Suvorexant: (Major) Coadministration of suvorexant and ceritinib is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
    Tacrolimus: (Major) Avoid coadministration of ceritinib with tacrolimus if possible due to the risk of QT prolongation; plasma concentrations of tacrolimus may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor tacrolimus whole blood trough concentrations at least 2 times on separate days during the first week after beginning concomitant therapy with ceritinib or after adjusting doses. Tacrolimus is a sensitive CYP3A4 substrate that can cause QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor significantly increased oral bioavailability of tacrolimus (14% vs. 30%) and decreased oral clearance (0.43 L/hour/kg vs. 0.148 L/hour/kg) compared to tacrolimus alone. Overall, intravenous clearance of tacrolimus was not significantly changed by coadministration with a strong CYP3A4 inhibitor, although it was highly variable between patients.
    Tadalafil: (Major) Avoid coadministration of tadalafil and ceritinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ceritinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as ceritinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
    Tamoxifen: (Major) Avoid coadministration of ceritinib with tamoxifen if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Tamsulosin: (Major) Concurrent use of tamsulosin and ceritinib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 like ceritinib are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively.
    Telavancin: (Major) Avoid coadministration of ceritinib with telavancin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Telavancin is also associated with QT prolongation.
    Telithromycin: (Major) Avoid coadministration of telithromycin with ceritinib due to the risk of increased telithromycin exposure; increased plasma concentrations of ceritinib and QT prolongation may also occur. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Telithromycin is also associated with QT prolongation and torsade de pointes (TdP). Concentration-dependent QT prolongation has been reported with ceritinib therapy. In the presence of strong inhibitors, the Cmax of telithromycin increased up to 51% and the AUC increased up to 95%. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    Temsirolimus: (Major) Avoid coadministration of ceritinib with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week and monitor for temsirolimus-related adverse reactions. Allow a washout period of approximately 1 week after discontinuation of ceritinib before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Terbinafine: (Major) Monitor for an increase in terbinafine-related adverse reactions if coadministration with ceritinib is necessary. Terbinafine is a CYP3A4 and CYP2C9 substrate. Ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Coadministration with a moderate CYP3A4 and CYP2C9 inhibitor increased the Cmax and AUC of terbinafine by 52% and 69%, respectively.
    Terbutaline: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 tetrabenazine with ceritinib due to the risk of QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Concentration-dependent QT prolongation has been reported with ceritinib treatment.
    Tezacaftor; Ivacaftor: (Major) If ceritinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ceritinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Theophylline, Aminophylline: (Major) Avoid the use of ceritinib, a time-dependent inhibitor of CYP3A4, with CYP3A4 substrates that have a narrow therapeutic index, such as theophylline, aminophylline as theophylline exposure may be increased. If co-administration is unavoidable, consider a theophylline dose reduction and monitor for theophylline toxicity.
    Thioridazine: (Severe) Thioridazine is contraindicated for use along with agents such as ceritinib that may prolong the QT interval and increase the risk of torsades de pointes (TdP), and/or cause orthostatic hypotension when combined with a phenothiazine. Thioridazine is associated with a well-established risk of QT prolongation and TdP, and ceritinib is associated with concentration-dependent QT prolongation.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and ceritinib if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; ceritinib is a strong CYP3A4 inhibitor.
    Ticagrelor: (Major) Avoid coadministration of ticagrelor with ceritinib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Timolol: (Major) Avoid coadministration of ceritinib with timolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; timolol also causes bradycardia.
    Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with ceritinib is necessary. Tinidazole is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Tiotropium; Olodaterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Tipranavir: (Major) Avoid coadministration of ceritinib with tipranavir due to increased exposure to ceritinib; tipranavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for treatment-related adverse reactions. After tipranavir is discontinued, resume the dose of ceritinib taken prior to initiating tipranavir. Ceritinib is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Tipranavir is a sensitive CYP3A4 substrate, as well as a strong CYP3A4 inhibitor.
    Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ceritinib. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving tofacitinib 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving tofacitinib extended-release 11 mg once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Tolterodine: (Major) Avoid coadministration of ceritinib with tolterodine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Tolterodine is a CYP3A4 substrate that can also cause concentration-dependent QT prolongation, especially in CYP2D6 poor metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
    Tolvaptan: (Severe) The concomitant use of tolvaptan and ceritinib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ceritinib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Toremifene: (Major) Avoid coadministration of ceritinib with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to treatment. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ceritinib is a strong CYP3A4 inhibitor that has also been reported to cause concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Torsemide: (Moderate) Monitor diuretic effect and blood pressure if torsemide is used in combination with ceritinib; adjust the dose of torsemide if necessary. Ceritinib is a weak CYP2C9 inhibitor and torsemide is primarily metabolized by CYP2C9.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with ceritinib due to significantly increased trabectedin exposure. Trabectedin is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the systemic exposure of a single dose of trabectedin by 66%.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ceritinib 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 ceritinib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Trandolapril; Verapamil: (Major) Avoid coadministration of ceritinib with verapamil if possible due to the risk of additive bradycardia; plasma concentrations of verapamil may also increase. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Verapamil is a CYP3A4 substrate that causes bradycardia. Ceritinib is a strong CYP3A4 inhibitor that also causes bradycardia.
    Trazodone: (Major) Avoid coadministration of ceritinib with trazodone due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of trazodone may also be increased resulting in increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Trazodone is a CYP3A4 substrate that can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Triamcinolone: (Moderate) Ceritinib, a strong CYP3A4 inhibitor, may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
    Triazolam: (Severe) Concomitant use of ceritinib with triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Triazolam is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Consider safer alternatives if a benzodiazepine must be administered in combination with ceritinib. Benzodiazepines not metabolized by the CYP3A4 enzyme (e.g., lorazepam, oxazepam) are less likely to be affected by strong CYP3A4 inhibitors.
    Trifluoperazine: (Minor) 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, such a ceritinib.
    Trimipramine: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and trimipramine; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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 ceritinib with triptorelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc 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.
    Ulipristal: (Moderate) Use of ulipristal and ceritinib may increase the plasma concentration of ulipristal but is not likely to be significant for single-dose emergency contraceptive use. Avoid ceritinib if ulipristal is given chronically for hormonal conditions. Concomitant use of ulipristal, a CYP3A4 substrate, and ceritinib, a strong CYP3A4 inhibitor, may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events. Coadministration with another strong CYP3A4 inhibitor increased ulipristal exposure by 5.9-fold and increased the AUC of monodemethyl-ulipristal acetate by 2.4-fold.
    Umeclidinium; Vilanterol: (Moderate) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and long-acting beta-agonists; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. 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.
    Upadacitinib: (Moderate) Use upadacitinib with caution in patients receiving chronic treatment with ceritinib as upadacitinib exposure and adverse effects may be increased. Upadacitinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Concurrent use of upadacitinib with a strong inhibitor increased upadacitinib exposure by 75%.
    Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ceritinib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
    Vandetanib: (Major) Avoid coadministration of vandetanib with ceritinib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. Both drugs can prolong the QT interval in a concentration-dependent manner; sudden death and TdP have been reported in patients receiving vandetanib.
    Vardenafil: (Major) Due to increased vardenafil exposure, do not use vardenafil orally disintegrating tablets with ceritinib. If possible, avoid concomitant use of vardenafil oral tablets with ceritinib due to the potential for prolongation of the QT interval and increased vardenafil exposure. If concomitant use of ceritinib and vardenafil oral tablets is unavoidable, decrease the vardenafil dosage and periodically monitor ECGs and electrolytes. Vardenafil is a sensitive CYP3A4 substrate that can produce an increase in QTc interval at both therapeutic and supratherapeutic doses. Ceritinib is a strong CYP3A4 inhibitor that has been reported to cause concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of vardenafil in healthy volunteers by 10-fold and 4-fold, respectively.
    Vemurafenib: (Major) Avoid coadministration of vemurafenib with ceritinib if possible due to increased plasma concentrations of vemurafenib and the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and periodically monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Vemurafenib is a CYP3A4 substrate that has been associated with QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Although the effect of strong CYP3A4 inhibitors on the systemic exposure of vemurafenib has not been evaluated in vivo, vemurafenib plasma concentrations may be expected to increase.
    Venetoclax: (Severe) Coadministration of ceritinib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ceritinib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Venlafaxine: (Major) Avoid coadministration of ceritinib with venlafaxine if possible due to the risk of QT prolongation; plasma concentrations of venlafaxine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for venlafaxine-related adverse reactions. Venlafaxine is a CYP3A4 substrate that is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has been reported with postmarketing use. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Verapamil: (Major) Avoid coadministration of ceritinib with verapamil if possible due to the risk of additive bradycardia; plasma concentrations of verapamil may also increase. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Verapamil is a CYP3A4 substrate that causes bradycardia. Ceritinib is a strong CYP3A4 inhibitor that also causes bradycardia.
    Vilazodone: (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with ceritinib is necessary; the original dose of vilazodone can be resumed if ceritinib is discontinued. Vilazodone is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vilazodone exposure by 50%.
    Vinblastine: (Moderate) Monitor for vinblastine-related adverse reactions if coadministration with ceritinib is necessary; concomitant use may cause an earlier onset and/or increased severity of side effects. Ceritinib is a strong CYP3A4 inhibitor and vinblastine is primarily metabolized by CYP3A4.
    Vincristine Liposomal: (Major) Avoid coadministration of vincristine with ceritinib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Vincristine: (Major) Avoid coadministration of vincristine with ceritinib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 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 ceritinib is necessary. Vinorelbine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar with ceritinib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Voriconazole: (Severe) The concurrent use of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ceritinib, is contraindicated. Both ceritinib and voriconazole are CYP3A4 substrates and strong CYP3A4 inhibitors. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Concentration-dependent QT prolongation has been reported with ceritinib therapy.
    Vorinostat: (Major) Avoid coadministration of ceritinib with vorinostat if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Vorinostat is also associated with QT prolongation.
    Voxelotor: (Major) Avoid coadministration of voxelotor and ceritinib as concurrent use may increase voxelotor exposure and lead to increased toxicity. If coadministration is unavoidable, reduce voxelotor dosage to 1,000 mg PO once daily. Voxelotor is a substrate of CYP3A4; ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase voxelotor exposure by 42% to 83%.
    Warfarin: (Major) Avoid coadministration of ceritinib with warfarin due to increased warfarin exposure. If concomitant use is unavoidable, increase the frequency of PT/INR monitoring and watch for bleeding complications; a dosage adjustment may be necessary. Ceritinib is a weak CYP2C9 and CYP3A4 inhibitor. Warfarin is a CYP2C9 substrate with a narrow therapeutic index; additionally, the R-isomer of warfarin, which has less anticoagulant activity and slower clearance, is metabolized by CYP3A4. Coadministration with ceritinib increased the S-warfarin AUC by 54% with no change in Cmax compared to warfarin alone.
    Zaleplon: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with ceritinib is necessary. Zaleplon is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with ceritinib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of ceritinib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
    Zileuton: (Moderate) Monitor for an increase in zileuton-related adverse reactions if coadministration with ceritinib is necessary. Zileuton is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Ziprasidone: (Major) Concomitant use of ziprasidone and ceritinib 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. Concentration-dependent QT prolongation has been reported with ceritinib.
    Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with ceritinib is necessary. Zolpidem is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of zolpidem by 34% to 70%.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during ceritinib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, ceritinib can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who become pregnant while receiving ceritinib should be apprised of the potential hazard to the fetus. An embryo-fetal development study in pregnant rats and rabbits found dose-related skeletal anomalies including delayed ossifications and skeletal variations after ceritinib exposure less than 0.5-fold and 0.015-fold the human exposure by AUC at the recommended dose, respectively. At 0.13-fold the human exposure by AUC at the recommended dose, a low incidence of visceral anomalies including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery occurred in pregnant rabbits. Maternal toxicity, abortion, and embryolethality were also reported with higher exposures in animal studies.

    Counsel patients about the reproductive risk and contraception requirements during ceritinib treatment. Ceritinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with ceritinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of ceritinib. Based on the potential for male-mediated teratogenicity, males with female partners of reproductive potential should use condoms during treatment with ceritinib and for 3 months after the last dose. Women who become pregnant while receiving ceritinib or while their partner is receiving ceritinib should be apprised of the potential hazard to the fetus. There are no data regarding the effect of ceritinib on human fertility. In general toxicology studies conducted in monkeys and rats at exposures greater than or equal to 0.5-fold and 1.5-fold, respectively of the human exposure at the recommended dose, there were no adverse effects on male or female reproductive organs.

    MECHANISM OF ACTION

    Ceritinib is an oral kinase inhibitor primarily targeting anaplastic lymphoma kinase (ALK); additional targets include insulin-like growth factor 1 (IFG-1) receptor, insulin receptor (InsR), and ROS1. The inhibition of IGF-1 receptor is 50 times less potent than inhibition of ALK. In in vitro and in vivo assays, ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. Ceritinib also exhibited dose-dependent anti-tumor activity in mice bearing EML4-ALK-positive NSCLC xenografts with resistance to crizotinib. Unlike crizotinib, ceritinib does not inhibit the kinase activity of MET.

    PHARMACOKINETICS

    Ceritinib is administered orally. Ceritinib is approximately 97% protein bound in serum, independent of drug concentration. The geometric mean apparent volume of distribution is 4,230 L after a single 750-mg dose of ceritinib was given under fasted conditions. There is a preferential distribution to red blood cells relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35. The geometric mean apparent plasma terminal half-life of ceritinib was 41 hours, with steady-state reached by approximately day 15 and a geometric mean accumulation ratio of 6.2 after 3 weeks. The pharmacokinetics of ceritinib are nonlinear, with a geometric mean apparent clearance of 88.5 L/hour after a single dose and 33.2 L/hour after daily dosing. Ceritinib crossed the blood-brain barrier in rats with a blood-to-brain exposure ratio of approximately 15%. After oral administration of a radiolabeled dose, fecal elimination comprises 92% of a radiolabeled dose (68% as unchanged drug) while 1.3% of a dose is recovered in the urine.[57094]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9
    Ceritinib is primarily metabolized by CYP3A4; the parent drug is the main circulating component (82%) in human plasma following oral administration of a single radiolabeled dose. Ceritinib is also a strong CYP3A4 inhibitor and a weak inhibitor of CYP2C9. Ceritinib is a substrate of P-glycoprotein (P-gp) in vitro.[57094]

    Oral Route

    After a single oral dose of ceritinib, peak plasma levels (Cmax) were achieved at approximately 4 to 6 hours; the AUC and Cmax increased in a dose-proportional manner after a single dose of 50 mg to 750 mg on an empty stomach. Systemic exposure increased in a greater than dose proportional manner after repeat doses of 50 mg to 750 mg once daily on an empty stomach.[57094]
     
    Food increases the systemic exposure of ceritinib. In healthy subjects, administration with a high-fat meal (approximately 1,000 calories and 58 g fat) increased the AUC and Cmax of a single 500-mg dose of ceritinib by 73% and 41%, respectively, compared to fasting conditions; the AUC and Cmax of a single 750-mg dose of ceritinib increased by 64% and 58%, respectively, when administered with a low-fat meal. Administration with a low-fat meal (approximately 330 calories and 9 g fat) increased the AUC and Cmax of a single 500-mg dose of ceritinib by 58% and 43%, respectively, compared to fasting conditions; the AUC and Cmax of a single 750-mg dose of ceritinib increased by 39% and 42%, respectively, when administered with a low-fat meal. In a dose-optimization study (ASCEND-8), there was no clinically meaningful difference in the systemic steady-state AUC values of ceritinib 450 mg once daily with food (100 to 500 calories and 1.5 to 15 g fat) or ceritinib 750 mg once daily on an empty stomach.[57094]