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    Small Molecule Antineoplastic Hedgehog Pathway Inhibitors

    BOXED WARNING

    Intrauterine fetal death, pregnancy

    Glasdegib may cause intrauterine fetal death or severe birth defects when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking glasdegib. Discuss the potential hazard to the fetus if glasdegib is used during pregnancy or if a patient becomes pregnant while taking this drug. Advise patients to immediately notify their healthcare provider if they become pregnant or think they might be pregnant, or if a female partner of a male patient taking glasdegib becomes pregnant. Pregnancies should be reported to Pfizer at 1-800-438-1985. Although there are no human data on the use of glasdegib in pregnant women, it was embryotoxic, fetotoxic, and teratogenic in animals at maternal exposures lower than the human exposures at the recommended dose of 100 mg/day. Teratogenic effects (e.g., craniofacial malformations, malformed limbs, paws/digits, trunk and tail, dilation of brain, malpositioned/malformed eyes, misshapen head, small tongue, absent palate, teeth and viscera, diaphragmatic hernia, edema, heart defects, rib and vertebral abnormalities, and malformed or absent structures in the appendicular skeleton) occurred when pregnant rats or rabbits received a dose resulting in approximately 0.6 times the exposure that was observed in humans who received the recommended dose.[63777]

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

    Counsel patients about the reproductive risk and contraception requirements during glasdegib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. These women should use effective contraception during therapy and for at least 30 days after the final glasdegib dose. It is not known if glasdegib is present in semen; therefore, male patients should not donate semen during glasdegib therapy or for at least 30 days after the last dose. Due to the risk of male-mediated teratogenicity, male patients should use effective contraception including a condom, even after a vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for at least 30 days after the final glasdegib dose. The risk of infertility with glasdegib has not been studied in humans, although findings from animal studies suggest that impaired fertility may occur in male patients. Advise male patients to seek advice on fertility preservation prior to treatment with glasdegib. In male rats, testicular changes including partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration occurred following glasdegib doses resulting in about 6.6-times the AUC value observed in patients at the recommended human dose; hypospermatogenesis did not recover.[63777]

    DEA CLASS

    Rx

    DESCRIPTION

    Oral hedgehog pathway inhibitor
    Used in combination with low-dose cytarabine for newly-diagnosed AML in patients who are elderly or have comorbidities that make them ineligible for intensive chemotherapy
    May cause embryo-fetal death or severe birth defects when administered during pregnancy

    COMMON BRAND NAMES

    Daurismo

    HOW SUPPLIED

    Daurismo Oral Tab: 25mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of acute myelogenous leukemia (AML).
    NOTE: Glasdegib has been designated an orphan drug by the FDA for the treatment of AML.
    For the treatment of newly-diagnosed AML in patients who are 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy, in combination with low-dose cytarabine.
    Oral dosage
    Adults

    100 mg orally once daily in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10. Repeat treatment cycles every 28 days until disease progression. Continue therapy for a minimum of 6 cycles in patients who do not have unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity. At a median follow-up time of about 20 months, the overall survival time was significantly improved in patients who received glasdenib plus low-dose cytarabine (n = 77) compared with low-dose cytarabine alone (n = 38) (8.3 months vs. 4.3 months; hazard ratio = 0.46; 95% CI, 0.3 to 0.71; p = 0.0002) in a multicenter, open-label, randomized trial (the BRIGHT AML 1003 trial). Patients in this study were 55 years of age or older with newly-diagnosed AML and had at least 1 of the following criteria: age greater than 75 years; severe cardiac disease; a baseline Eastern Cooperative Oncology Group performance status of 2; or a baseline serum creatinine level greater than 1.3 mg/dL.[63777]

    MAXIMUM DOSAGE

    Adults

    100 mg/day PO.

    Geriatric

    100 mg/day PO.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in mild hepatic impairment are not available; it appears that no initial dosage adjustments are needed. Glasdegib has not been evaluated in patients with moderate to severe hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in mild or moderate renal impairment are not available; it appears that no initial dosage adjustments are needed. Glasdegib has not been evaluated in patients with severe renal impairment.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take glasdegib with or without food at about the same time each day.
    Swallow whole; do not split or crush tablets.
    If vomiting occurs, do not take an additional dose; wait to take the next dose at the regularly scheduled time.
    If a dose is missed, take within 12 hours of missing the dose. If more than 12 hours have passed, skip the dose of the day and take the dose the next day at the scheduled time.[63777]

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, electrolyte imbalance, females, geriatric, heart failure, hypertension, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease, ventricular arrhythmias

    QT prolongation and ventricular arrhythmias (e.g., ventricular fibrillation and ventricular tachycardia) have been reported with glasdegib therapy. Therapy interruption and a dose reduction are necessary in patients who develop a QTc interval greater than 500 milliseconds (msec) evaluated on at least 2 separate electrocardiograms (ECGs) during glasdegib therapy; permanently discontinue glasdegib in patients who develop QT prolongation with a life-threatening arrhythmia. Obtain an ECG prior to starting glasdegib, approximately 1 week after the first dose, and then once monthly for the next 2 months. Repeat the ECG if any abnormal results are observed. Some patients may require more frequent ECG monitoring. Monitor electrolytes prior to starting glasdegib and at least once weekly for the first month of therapy, then monitor electrolytes once monthly for the duration of therapy. In patients who develop QT prolongation greater than 480 msec evaluated on at least 2 separate ECGs, review and adjust concomitant medications with known QT interval-prolonging effects, monitor electrolytes and supplement as clinically indicated, and obtain an ECG at least weekly for 2 weeks following resolution of QTc prolongation to 480 msec or less. More frequent monitoring is recommended in patients with congenital long QT syndrome, congestive heart failure, electrolyte imbalance/abnormalities (e.g., hypomagnesemia, hypokalemia, hypocalcemia), or who are receiving medications known to prolong the QT interval.[63777] Use glasdegib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, bradycardia, myocardial infarction, hypertension, coronary artery disease, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, and patients with diabetes mellitus, thyroid disease, malnutrition, or alcoholism may also be at increased risk for QT prolongation.[28432] [28457] [56959] [56961] [56592]

    Neutropenia, thrombocytopenia

    Prolonged neutropenia and thrombocytopenia have been reported with glasdegib therapy. Monitor complete blood counts prior to starting glasdegib and at least once weekly for the first month of therapy. Permanently discontinue glasdegib and low-dose cytarabine therapy in patients who have an absolute neutrophil count less than 0.5 X 109 cells/L or a platelet count less than 10 X 109 cells/L lasting more than 42 days in the absence of disease.[63777]

    Renal impairment

    Monitor renal function (e.g., serum creatinine and BUN levels) prior to starting glasdegib and at least once weekly for the first month of therapy, then monitor renal function once monthly for the duration of therapy. Glasdegib has not been evaluated in patients with severe renal impairment (defined as a creatinine clearance of 15 to 29 mL/min).[63777]

    Hepatic disease

    Monitor hepatic function (e.g., liver function tests) prior to starting glasdegib and at least once weekly for the first month of therapy. Glasdegib has not been evaluated in patients with moderate (i.e., total bilirubin level 1.5- to 3-times the upper limit of normal (ULN) and any AST level) or severe (i.e., total bilirubin greater than 3-times the ULN and any AST level) hepatic impairment. Patient with hepatic disease may be at increased risk for QT prolongation.[63777]

    Muscle cramps

    Monitor serum creatine phosphokinase levels prior to starting glasdegib and as clinically indicated during therapy (e.g., if muscle symptoms such as muscle cramps are reported).

    Blood donation

    Blood donation or blood product donation is not recommended during glasdegib therapy and for at least 30 days after the last dose.

    Intrauterine fetal death, pregnancy

    Glasdegib may cause intrauterine fetal death or severe birth defects when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking glasdegib. Discuss the potential hazard to the fetus if glasdegib is used during pregnancy or if a patient becomes pregnant while taking this drug. Advise patients to immediately notify their healthcare provider if they become pregnant or think they might be pregnant, or if a female partner of a male patient taking glasdegib becomes pregnant. Pregnancies should be reported to Pfizer at 1-800-438-1985. Although there are no human data on the use of glasdegib in pregnant women, it was embryotoxic, fetotoxic, and teratogenic in animals at maternal exposures lower than the human exposures at the recommended dose of 100 mg/day. Teratogenic effects (e.g., craniofacial malformations, malformed limbs, paws/digits, trunk and tail, dilation of brain, malpositioned/malformed eyes, misshapen head, small tongue, absent palate, teeth and viscera, diaphragmatic hernia, edema, heart defects, rib and vertebral abnormalities, and malformed or absent structures in the appendicular skeleton) occurred when pregnant rats or rabbits received a dose resulting in approximately 0.6 times the exposure that was observed in humans who received the recommended dose.[63777]

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

    Counsel patients about the reproductive risk and contraception requirements during glasdegib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. These women should use effective contraception during therapy and for at least 30 days after the final glasdegib dose. It is not known if glasdegib is present in semen; therefore, male patients should not donate semen during glasdegib therapy or for at least 30 days after the last dose. Due to the risk of male-mediated teratogenicity, male patients should use effective contraception including a condom, even after a vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for at least 30 days after the final glasdegib dose. The risk of infertility with glasdegib has not been studied in humans, although findings from animal studies suggest that impaired fertility may occur in male patients. Advise male patients to seek advice on fertility preservation prior to treatment with glasdegib. In male rats, testicular changes including partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration occurred following glasdegib doses resulting in about 6.6-times the AUC value observed in patients at the recommended human dose; hypospermatogenesis did not recover.[63777]

    Breast-feeding

    It is not known if glasdegib or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or milk production. Because there is a potential for adverse reactions in nursing infants from glasdegib, women should discontinue breast-feeding during glasdegib therapy and for at least 30 days after the last dose.[63777]

    ADVERSE REACTIONS

    Severe

    anemia / Delayed / 0-41.0
    neutropenia / Delayed / 0-31.0
    thrombocytopenia / Delayed / 0-30.0
    hyperkalemia / Delayed / 16.0-16.0
    asthenia / Delayed / 0-14.0
    fatigue / Early / 14.0-14.0
    atrial fibrillation / Early / 0-13.0
    bradycardia / Rapid / 0-13.0
    dyspnea / Early / 11.0-11.0
    hypoxia / Early / 0-11.0
    bronchospasm / Rapid / 0-11.0
    infection / Delayed / 0-7.0
    hyponatremia / Delayed / 7.0-7.0
    retinal hemorrhage / Delayed / 0-6.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-6.0
    intracranial bleeding / Delayed / 0-6.0
    hematemesis / Delayed / 0-6.0
    disseminated intravascular coagulation (DIC) / Delayed / 0-6.0
    hematoma / Early / 0-6.0
    hemoptysis / Delayed / 0-6.0
    retroperitoneal bleeding / Delayed / 0-6.0
    bleeding / Early / 6.0-6.0
    hematuria / Delayed / 0-6.0
    ocular hemorrhage / Delayed / 0-6.0
    GI bleeding / Delayed / 0-6.0
    subdural hematoma / Early / 0-6.0
    oliguria / Early / 0-5.0
    renal failure (unspecified) / Delayed / 0-5.0
    sinus tachycardia / Rapid / 0-4.0
    hyperbilirubinemia / Delayed / 4.0-4.0
    diarrhea / Early / 4.0-4.0
    colitis / Delayed / 0-4.0
    arthralgia / Delayed / 0-2.0
    back pain / Delayed / 0-2.0
    myalgia / Early / 0-2.0
    musculoskeletal pain / Early / 2.0-2.0
    bone pain / Delayed / 0-2.0
    skin ulcer / Delayed / 0-2.0
    erythema / Early / 0-2.0
    rash / Early / 2.0-2.0
    pruritus / Rapid / 0-2.0
    maculopapular rash / Early / 0-2.0
    vomiting / Early / 2.0-2.0
    chest pain (unspecified) / Early / 1.0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    nausea / Early / 1.0-1.0
    oral ulceration / Delayed / 0-1.0
    constipation / Delayed / 1.0-1.0
    stomatitis / Delayed / 0-1.0
    esophagitis / Delayed / 0-1.0
    fever / Early / 1.0-1.0
    dizziness / Early / 1.0-1.0
    ventricular fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    nephrotoxicity / Delayed / Incidence not known

    Moderate

    hypomagnesemia / Delayed / 33.0-33.0
    fluid retention / Delayed / 0-30.0
    peripheral edema / Delayed / 0-30.0
    edema / Delayed / 30.0-30.0
    hypokalemia / Delayed / 15.0-15.0
    QT prolongation / Rapid / 0-5.0

    Mild

    ecchymosis / Delayed / 0-30.0
    injection site reaction / Rapid / 0-30.0
    epistaxis / Delayed / 0-30.0
    petechiae / Delayed / 0-30.0
    purpura / Delayed / 0-30.0
    anorexia / Delayed / 21.0-21.0
    dysgeusia / Early / 21.0-21.0
    abdominal pain / Early / 19.0-19.0
    cough / Delayed / 18.0-18.0
    muscle cramps / Delayed / 15.0-15.0
    weight loss / Delayed / 13.0-13.0
    headache / Early / 12.0-12.0
    alopecia / Delayed / 0-10.0

    DRUG INTERACTIONS

    Aclidinium; Formoterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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: (Minor) Consider increased frequency of ECG monitoring if coadministration of glasdegib and short-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider increased frequency of ECG monitoring if coadministration of glasdegib and short-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Alfuzosin: (Major) Avoid coadministration of glasdegib with alfuzosin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid coadministration of glasdegib with amiodarone due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Amiodarone, a Class III antiarrhythmic agent, is associated with a well established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of glasdegib with clarithromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of glasdegib with clarithromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Anagrelide: (Major) Do not use anagrelide with other drugs that prolong the QT interval, such as glasdegib. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were observed in healthy subjects. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Apalutamide: (Major) Avoid coadministration of glasdegib and apalutamide due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Apomorphine: (Major) Avoid coadministration of glasdegib with apomorphine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Arformoterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 coadministration of glasdegib with aripiprazole due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid coadministration of glasdegib with arsenic trioxide due to the potential for additive QT prolongation. Discontinue glasdegib or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
    Artemether; Lumefantrine: (Major) Avoid coadministration of glasdegib with artemether due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Artemether is also associated with prolongation of the QT interval. (Major) Avoid coadministration of glasdegib with lumefantrine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Asenapine: (Major) Avoid coadministration of glasdegib with asenapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Asenapine has also been associated with QT prolongation.
    Atazanavir: (Major) Consider an alternative to atazanavir 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. Glasdegib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Atazanavir; Cobicistat: (Major) Consider an alternative to atazanavir 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. Glasdegib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. (Major) Consider an alternative to cobicistat 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. Glasdegib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Atomoxetine: (Major) Avoid coadministration of glasdegib with atomoxetine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of glasdegib and phenobarbital due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Azithromycin: (Major) Avoid coadministration of glasdegib with azithromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Avoid coadministration of glasdegib with bedaquiline due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Bedaquiline has been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of glasdegib and phenobarbital due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of glasdegib with metronidazole due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of glasdegib with metronidazole due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Budesonide; Formoterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Buprenorphine: (Major) Avoid coadministration of glasdegib with buprenorphine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buprenorphine; Naloxone: (Major) Avoid coadministration of glasdegib with buprenorphine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Carbamazepine: (Major) Avoid coadministration of glasdegib and carbamazepine due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Ceritinib: (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.
    Chloramphenicol: (Major) Consider an alternative to chloramphenicol 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. Glasdegib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Chloroquine: (Major) Avoid coadministration of glasdegib with chloroquine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Chlorpromazine: (Major) Avoid coadministration of glasdegib with chlorpromazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Major) Avoid coadministration of glasdegib with ciprofloxacin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Coadministration of glasdegib and cisapride is contraindicated due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride.
    Citalopram: (Major) Avoid coadministration of glasdegib with citalopram due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Citalopram causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid coadministration of glasdegib with clarithromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Clofazimine: (Major) Avoid coadministration of glasdegib with clofazimine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Clomipramine: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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).
    Clozapine: (Major) Avoid coadministration of glasdegib with clozapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Major) Consider an alternative to cobicistat 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. Glasdegib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of glasdegib with promethazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Avoid coadministration of glasdegib with promethazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Conivaptan: (Major) Consider an alternative to conivaptan 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. Glasdegib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Crizotinib: (Major) Avoid coadministration of glasdegib with crizotinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; monitor with increased frequency in patients at increased risk for QT prolongation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Darunavir: (Major) Consider an alternative to darunavir 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. Glasdegib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Darunavir; Cobicistat: (Major) Consider an alternative to cobicistat 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. Glasdegib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. (Major) Consider an alternative to darunavir 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. Glasdegib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Consider an alternative to cobicistat 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. Glasdegib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. (Major) Consider an alternative to darunavir 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. Glasdegib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider an alternative to ritonavir 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. Glasdegib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Dasatinib: (Major) Avoid coadministration of glasdegib with dasatinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Degarelix: (Major) Avoid coadministration of glasdegib with degarelix due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QTc prolongation has also been reported with the use of degarelix.
    Delavirdine: (Major) Consider an alternative to delavirdine 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. Glasdegib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Desflurane: (Major) Avoid coadministration of glasdegib with halogenated anesthetics due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with deutetrabenazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. For patients taking a deutetrabenazine dosage more than 24 mg/day and glasdegib, assess the QTc interval before and after increasing the deutetrabenazine or glasdegib dosage. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Clinically relevant QTc prolongation may occur with deutetrabenazine.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of glasdegib with promethazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of glasdegib with quinidine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
    Disopyramide: (Major) Avoid coadministration of glasdegib with disopyramide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
    Dofetilide: (Major) Avoid coadministration of glasdegib with dofetilide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Dolasetron: (Major) Avoid coadministration of glasdegib with dolasetron due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of glasdegib with rilpivirine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) Avoid coadministration of glasdegib with donepezil due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Donepezil; Memantine: (Major) Avoid coadministration of glasdegib with donepezil due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Doxepin: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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).
    Dronedarone: (Severe) Coadministration of glasdegib and dronedarone is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as glasdegib. 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. Monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Efavirenz: (Major) Avoid coadministration of glasdegib with efavirenz due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QTc prolongation has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of glasdegib with efavirenz due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QTc prolongation has also been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of glasdegib with efavirenz due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QTc prolongation has also been observed with the use of efavirenz.
    Eliglustat: (Major) Avoid coadministration of glasdegib with eliglustat due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Consider an alternative to cobicistat 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. Glasdegib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider an alternative to cobicistat 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. Glasdegib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of glasdegib with rilpivirine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of glasdegib with rilpivirine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of glasdegib with encorafenib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with a dose-dependent prolongation of the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Enflurane: (Major) Avoid coadministration of glasdegib with halogenated anesthetics due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Halogenated anesthetics can also prolong the QT interval.
    Entrectinib: (Major) Avoid coadministration of glasdegib with entrectinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Entrectinib has been associated with QT prolongation.
    Enzalutamide: (Major) Avoid coadministration of glasdegib and enzalutamide due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Eribulin: (Major) Avoid coadministration of glasdegib with eribulin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Avoid coadministration of glasdegib with erythromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Erythromycin is associated with QT prolongation and torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of glasdegib with erythromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Erythromycin is associated with QT prolongation and torsade de pointes (TdP).
    Escitalopram: (Major) Avoid coadministration of glasdegib with escitalopram due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Ezogabine: (Major) Avoid coadministration of glasdegib with ezogabine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ezogabine has also been associated with QT prolongation.
    Fingolimod: (Major) Avoid coadministration of glasdegib with fingolimod due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with flecainide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Severe) Coadministration of glasdegib with fluconazole is contraindicated due to the potential for QT prolongation. Glasdegib is a CYP3A4 substrate that may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Fluoxetine: (Major) Avoid coadministration of glasdegib with fluoxetine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of glasdegib with fluoxetine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine (Major) Avoid coadministration of glasdegib with olanzapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Consider increased frequency of ECG monitoring if glasdegib and fluphenazine are coadministered due to the potential for additive effects on the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Fluticasone; Salmeterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with fluvoxamine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use.
    Formoterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider an alternative to fosamprenavir 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. Glasdegib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Foscarnet: (Major) Avoid coadministration of glasdegib with foscarnet due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of glasdegib and fosphenytoin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Gemifloxacin: (Major) Avoid coadministration of glasdegib with gemifloxacin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Do not exceed the recommended dose of gemifloxacin especially in patients with renal or hepatic impairment. Gemifloxacin may prolong the QT interval in some patients; the likelihood of QTc prolongation may increase with increasing dose of the drug. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of glasdegib with gemtuzumab ozogamicin due to the potential for additive QT prolongation. If coadministration cannot be avoided, obtain an ECG and serum electrolytes prior to the start of gemtuzumab. Increase the frequency of ECG monitoring during coadministration and monitor serum electrolytes as needed. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Avoid coadministration of glasdegib with gilteritinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Gilteritinib has been associated with QT prolongation.
    Glycopyrrolate; Formoterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with goserelin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Major) Avoid coadministration of glasdegib with granisetron due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Granisetron has also been associated with QT prolongation.
    Grapefruit juice: (Major) Grapefruit juice should not be consumed during glasdegib therapy. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. Glasdegib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Halogenated Anesthetics: (Major) Avoid coadministration of glasdegib with halogenated anesthetics due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of glasdegib with haloperidol due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Avoid coadministration of glasdegib with halogenated anesthetics due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Halogenated anesthetics can also prolong the QT interval.
    Histrelin: (Major) Avoid coadministration of glasdegib with histrelin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Glasdegib and hydroxychloroquine should not be coadministered due to additive risk of QT prolongation. Hydroxychloroquine prolongs the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Hydroxyzine: (Major) Avoid coadministration of glasdegib with hydroxyzine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
    Ibutilide: (Major) Avoid coadministration of glasdegib with ibutilide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider an alternative to idelalisib 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. Glasdegib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Iloperidone: (Major) Avoid coadministration of glasdegib with iloperidone due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Iloperidone has also been associated with QT prolongation.
    Imipramine: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider an alternative to indinavir 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. Glasdegib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of glasdegib with inotuzumab due to the potential for additive QT prolongation. If coadministration cannot be avoided, obtain ECGs prior to the start of treatment and increase the frequency of ECG monitoring during concurrent use. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Inotuzumab has also been associated with QT interval prolongation.
    Isoflurane: (Major) Avoid coadministration of glasdegib with halogenated anesthetics due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Halogenated anesthetics can also prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of glasdegib and rifampin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the glasdegib AUC by 70% in a drug interaction study.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of glasdegib and rifampin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the glasdegib AUC by 70% in a drug interaction study.
    Itraconazole: (Major) Avoid use of glasdegib during and for 2 weeks after discontinuation of itraconazole therapy due to the potential for increased glasdegib exposure and additive effects on the QT interval. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Ivosidenib: (Major) Avoid coadministration of glasdegib with ivosidenib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Monitor electrolytes and correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Ketoconazole: (Major) Consider an alternative to ketoconazole during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of ketoconazole increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Lapatinib: (Major) Avoid coadministration of glasdegib with lapatinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring; consider electrolyte monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Lefamulin: (Major) Avoid coadministration of lefamulin with glasdegib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin 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. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with glasdegib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Letermovir: (Moderate) Concurrent use of letermovir with glasdegib may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. Consider an alternative to letermovir if administered with cyclosporine during treatment with glasdegib. If coadministration of glasdegib with both letermovir and cyclosporine cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when administered with cyclosporine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Leuprolide: (Major) Avoid coadministration of glasdegib with leuprolide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of glasdegib with leuprolide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levalbuterol: (Minor) Consider increased frequency of ECG monitoring if coadministration of glasdegib and short-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Levofloxacin: (Major) Avoid coadministration of glasdegib with levofloxacin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Major) Avoid coadministration of glasdegib with lithium due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of glasdegib with lofexidine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Lofexidine also prolongs the QT interval.
    Long-acting beta-agonists: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with loperamide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Major) Avoid coadministration of glasdegib with loperamide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Consider an alternative to lopinavir; ritonavir during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Lopinavir; ritonavir is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. (Major) Consider an alternative to ritonavir 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. Glasdegib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of glasdegib and lumacaftor; ivacaftor due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of glasdegib and lumacaftor; ivacaftor due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with glasdegib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of glasdegib prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Maprotiline: (Major) Avoid coadministration of glasdegib with maprotiline due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Mefloquine: (Major) Avoid coadministration of glasdegib with mefloquine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine; Promethazine: (Major) Avoid coadministration of glasdegib with promethazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Metaproterenol: (Minor) Consider increased frequency of ECG monitoring if coadministration of glasdegib and short-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Methadone: (Major) Avoid coadministration of glasdegib with methadone due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Metronidazole: (Major) Avoid coadministration of glasdegib with metronidazole due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Avoid coadministration of glasdegib with midostaurin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation was reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Consider an alternative to mifepristone during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring; use the lowest effective dose of mifepristone. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Mifepristone is a strong CYP3A4 inhibitor that has been associated with dose-dependent prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. The clinical significance of inhibition of CYP3A4 with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mirtazapine: (Major) Avoid coadministration of glasdegib with mirtazapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid coadministration of glasdegib and mitotane due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Moxifloxacin: (Major) Avoid coadministration of glasdegib with moxifloxacin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nefazodone: (Major) Consider an alternative to nefazodone 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. Glasdegib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Nelfinavir: (Major) Consider an alternative to nelfinavir 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. Glasdegib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Nilotinib: (Major) Avoid administration of nilotinib with glasdegib due to the potential for additive QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Nortriptyline: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with octreotide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with ofloxacin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Avoid coadministration of glasdegib with olanzapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider an alternative to ritonavir 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. Glasdegib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Ondansetron: (Major) Avoid coadministration of glasdegib with ondansetron due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osimertinib: (Major) Avoid coadministration of glasdegib with osimertinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring and monitoring of electrolytes. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Oxaliplatin: (Major) Avoid coadministration of glasdegib with oxaliplatin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring and monitor electrolytes. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience.
    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 glasdegib with paliperidone if possible due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Paliperidone has also been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
    Panobinostat: (Major) Coadministration of glasdegib and panobinostat is not recommended due to the potential for additive QT prolongation. QT prolongation has been reported with panobinostat. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Pasireotide: (Major) Avoid coadministration of glasdegib with pasireotide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of glasdegib with pazopanib is not advised due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Pazopanib has been reported to prolong the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    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 glasdegib with pentamidine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Systemic pentamidine has been associated with QT prolongation.
    Perphenazine: (Minor) Consider increased frequency of ECG monitoring if glasdegib and perphenazine are coadministered due to the potential for additive effects on the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Perphenazine; Amitriptyline: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider increased frequency of ECG monitoring if glasdegib and perphenazine are coadministered due to the potential for additive effects on the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Phenobarbital: (Major) Avoid coadministration of glasdegib and phenobarbital due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of glasdegib with promethazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of glasdegib and phenytoin due to the potential for decreased glasdegib exposure. Glasdegib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Pimavanserin: (Major) Avoid coadministration of glasdegib with pimavanserin due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Pimavanserin may also cause QT prolongation.
    Pimozide: (Severe) Coadministration of glasdegib and pimozide is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Pirbuterol: (Minor) Consider increased frequency of ECG monitoring if coadministration of glasdegib and short-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with pitolisant due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Pitolisant also prolongs the QT interval.
    Posaconazole: (Severe) Coadministration of glasdegib and posaconazole is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP); glasdegib exposure may be increased further increasing the risk of QT prolongation. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Posaconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Primaquine: (Major) Avoid coadministration of glasdegib with primaquine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Primaquine also has the potential to prolong the QT interval.
    Primidone: (Major) Avoid coadministration of glasdegib and primidone due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Procainamide: (Major) Avoid coadministration of glasdegib with procainamide due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Minor) Consider increased frequency of ECG monitoring if glasdegib and prochlorperazine are coadministered due to the potential for additive effects on the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Promethazine: (Major) Avoid coadministration of glasdegib with promethazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of glasdegib with propafenone due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Protriptyline: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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).
    Quetiapine: (Major) Avoid coadministration of glasdegib with quetiapine due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Avoid coadministration of glasdegib with quinidine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
    Quinine: (Major) Avoid coadministration of glasdegib with quinine due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Major) Avoid coadministration of glasdegib with ranolazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Ribociclib: (Major) Consider an alternative to ribociclib during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Ribociclib; Letrozole: (Major) Consider an alternative to ribociclib during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Rifampin: (Major) Avoid coadministration of glasdegib and rifampin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the glasdegib AUC by 70% in a drug interaction study.
    Rilpivirine: (Major) Avoid coadministration of glasdegib with rilpivirine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) Avoid coadministration of glasdegib with risperidone due to the potential for additive QT prolongation. If coadministration cannot be avoided, consider the patient's underlying disease state(s) and additional potential risk factors. Monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes. Reports of QT prolongation and torsade de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
    Ritonavir: (Major) Consider an alternative to ritonavir 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. Glasdegib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Romidepsin: (Major) Avoid coadministration of glasdegib with romidepsin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with electrolyte monitoring and increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Romidepsin has also been reported to prolong the QT interval.
    Salmeterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib and saquinavir is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP); glasdegib exposure may be increased further increasing the risk of QT prolongation. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Saquinavir is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Sertraline: (Major) Avoid coadministration of glasdegib with sertraline due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with halogenated anesthetics due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Consider increased frequency of ECG monitoring if coadministration of glasdegib and short-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Siponimod: (Major) Avoid coadministration of siponimod and glasdegib due to the potential for additive 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. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Solifenacin: (Major) Avoid coadministration of glasdegib with solifenacin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Avoid coadministration of glasdegib with sorafenib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for QT prolongation with increased frequency of ECG monitoring, and monitor electrolytes; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Avoid coadministration of glasdegib with sotalol due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of glasdegib and St. John's wort due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; St. John's wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Sunitinib: (Major) Avoid coadministration of glasdegib with sunitinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Sunitinib can also prolong the QT interval.
    Tacrolimus: (Major) Avoid coadministration of glasdegib with tacrolimus due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tacrolimus also causes QT prolongation.
    Tamoxifen: (Major) Avoid coadministration of glasdegib with tamoxifen due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tamoxifen has 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.
    Telavancin: (Major) Avoid coadministration of glasdegib with telavancin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Telavancin has also been associated with QT prolongation.
    Telithromycin: (Major) Consider an alternative to telithromycin during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Telithromycin is a strong CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Terbutaline: (Minor) Consider increased frequency of ECG monitoring if coadministration of glasdegib and short-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with tetrabenazine due to the potential for additive QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Thioridazine: (Severe) Coadministration of glasdegib and thioridazine is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Tiotropium; Olodaterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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) Consider an alternative to tipranavir 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. Glasdegib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Tolterodine: (Major) Avoid coadministration of glasdegib with tolterodine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Major) Avoid coadministration of glasdegib with toremifene due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with electrolyte monitoring and increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trazodone: (Major) Avoid coadministration of glasdegib with trazodone due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Tricyclic antidepressants: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Consider increased frequency of ECG monitoring if glasdegib and trifluoperazine are coadministered due to the potential for additive effects on the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimipramine: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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 glasdegib with triptorelin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Umeclidinium; Vilanterol: (Moderate) Consider increased frequency of ECG monitoring if coadministration of glasdegib and long-acting beta-agonists is necessary. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
    Vandetanib: (Major) Avoid coadministration of vandetanib with glasdegib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, increase frequency of ECG monitoring and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Vardenafil: (Major) Avoid coadministration of glasdegib with vardenafil due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Avoid coadministration of glasdegib with vemurafenib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Vemurafenib has also been associated with QT prolongation.
    Venlafaxine: (Major) Avoid coadministration of glasdegib with venlafaxine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Voriconazole: (Major) Consider an alternative to voriconazole during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Coadministration of ketoconazole increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Vorinostat: (Major) Avoid coadministration of glasdegib with vorinostat due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Vorinostat therapy is also associated with a risk of QT prolongation.
    Ziprasidone: (Major) Concomitant use of ziprasidone and glasdegib should be avoided due to a 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. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.

    PREGNANCY AND LACTATION

    Pregnancy

    Counsel patients about the reproductive risk and contraception requirements during glasdegib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. These women should use effective contraception during therapy and for at least 30 days after the final glasdegib dose. It is not known if glasdegib is present in semen; therefore, male patients should not donate semen during glasdegib therapy or for at least 30 days after the last dose. Due to the risk of male-mediated teratogenicity, male patients should use effective contraception including a condom, even after a vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for at least 30 days after the final glasdegib dose. The risk of infertility with glasdegib has not been studied in humans, although findings from animal studies suggest that impaired fertility may occur in male patients. Advise male patients to seek advice on fertility preservation prior to treatment with glasdegib. In male rats, testicular changes including partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration occurred following glasdegib doses resulting in about 6.6-times the AUC value observed in patients at the recommended human dose; hypospermatogenesis did not recover.[63777]

    MECHANISM OF ACTION

    Glasdegib is a hedgehog (Hh) signaling pathway inhibitor. It works by binding to and inhibiting the transmembrane protein smoothened (SMO) that is necessary for Hh signal transduction. A greater inhibition in tumor size and a reduced number of CD45-positive and CD33-positive blasts in the bone marrow were observed with glasdegib plus low-dose cytarabine compared with glasdegib or low-dose cytarabine alone in a murine xenotransplant model of human acute myelogenous leukemia.[63777]

    PHARMACOKINETICS

    Glasdegib is administered orally. Plasma protein binding is 91% in vitro and the geometric mean (%CV) apparent volume of distribution is 188 L (20%) in patients with hematologic malignancies. Glasdegib accounts for 69% of the total circulating drug-related material in plasma. It is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. After a single oral radiolabeled dose of 100 mg, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) was eliminated in the feces. The mean half-life is 17.4 hours with a geometric mean (%CV) apparent clearance of 6.45 L/h (25%) after 100 mg daily dosing in patients with hematologic malignancies.[63777]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C8, UGT1A9, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein (MATE) 1, and MATE-2K
    Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Coadministration of a strong CYP3A4 inhibitor with glasdegib increased the glasdegib AUC by 2.4-fold and the Cmax by 1.4-fold. Coadministration with a strong CYP3A4 inducer decreased the glasdegib AUC by 70% and the Cmax by 35%. Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro. It does not induce CYP1A2, CYP2B6, or CYP3A4 in vitro. Glasdegib is a substrate of P-gp and BCRP, but the clinical significance is unknown. Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion protein (MATE) 1, and MATE-2K in vitro. It does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, or organic cation transporter (OCT) 2 in vitro.[63777]

    Oral Route

    The mean absolute bioavailability of glasdegib is 77% and the median time to peak concentrations (Tmax) at steady-state ranges from 1.3 to 1.8 hours. There is a dose proportional increase in peak concentrations (Cmax) and area under the curve over the dosing interval (AUCtau). Steady-state plasma concentrations are reached by 8 days of daily dosing and the mean accumulation ration ranges from 1.2 to 2.5 after once-daily dosing. The geometric mean (geometric coefficient of variation, %CV) of glasdegib Cmax is 1,252 ng/mL (44%) and the AUCtau is 17,210 ng x hr/mL (54%) in patients with cancer.[63777]
     
    Effects of food: A high-fat (500 to 600 fat calories), high-calorie (total 800 to 1000 calories) meal reduced the area under the curve over time to infinity (AUCinf) by 16% and the Cmax by 31%.[63777]