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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    An oral EGFR kinase inhibitor
    Used for the first-line treatment of patients with metastatic EGFR (exon 19 deletion or exon 21 (L858R) substitution) mutation-positive non-small cell lung cancer, or after progression on EGFR tyrosine kinase inhibitor therapy in patients with EGFR T790M mutation
    Serious adverse effects include QTc prolongation, neutropenia, and ILD/pneumonitis

    COMMON BRAND NAMES

    Tagrisso

    HOW SUPPLIED

    Tagrisso Oral Tab: 40mg, 80mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic EGFR mutation-positive non-small cell lung cancer (NSCLC).
    For the first-line treatment of metastatic EGFR (exon 19 deletion or exon 21 (L858R) substitution) mutation-positive non-small cell lung cancer (NSCLC).
    NOTE: Confirm the presence of a EGFR exon 19 deletion or exon 21 (L858R) substitution mutation in tumor specimens prior to initiation of treatment with osimertinib.
    Oral dosage
    Adults

    80 mg by mouth once daily, until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind clinical trial of previously untreated patients with metastatic EGFR (exon 19 deletion or exon 21 (L858R) substitution) mutation-positive NSCLC, treatment with osimertinib significantly improved median progression-free survival (PFS) compared with an EGFR tyrosine kinase inhibitor (TKI) (e.g., gefitinib or erlotinib) (18.9 months vs. 10.2 months). The overall response rate was 77% (complete response (CR), 2%) with a median duration of 17.6 months in the osimertinib arm compared with 69% (CR, 1%) and a median duration of 9.6 months in the EGFR TKI arm. Overall survival data were not yet mature.

    For the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC), after progression on or after EGFR tyrosine kinase inhibitor (TKI) therapy.
    NOTE: Confirm the presence of a T790M EGFR mutation in tumor specimens prior to initiation of treatment with osimertinib. If a tumor biopsy cannot be obtained, test for the T790M EGFR mutation in plasma specimens; however, if not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing.
    Oral dosage
    Adults

    80 mg by mouth once daily, until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, open-label, phase 3 clinical trial (AURA3), patients with T790M-positive advanced NSCLC with disease progression after first-line EGFR-TKI therapy, treatment with osimertinib significantly improved median progression-free survival (PFS) compared with pemetrexed plus carboplatin or cisplatin (10.1 vs. 4.4 months); the benefit of osimertinib on PFS was consistent among patients with CNS metastases (8.5 vs. 4.2 months). The overall response rate (ORR) was also significantly better for patient who received osimertinib compared with pemetrexed plus platinum therapy (65% vs. 29%), with a median duration of 11 months versus 4.2 months, respectively. The ORR for patients with CNS tumors was 57% (complete response (CR), 7%) in patients treated with osimertinib compared with 25% (CR, 0%) in patients who received chemotherapy, with 57% of osimertinib patients maintaining a CNS response of greater than or equal to 6 months and 12% maintaining a response of 9 months or longer; no patients treated with chemotherapy maintained a response longer than 6 months. Data for overall survival were not yet mature.

    MAXIMUM DOSAGE

    Adults

    80 mg/day PO.

    Geriatric

    80 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild to moderate hepatic impairment (Child-Pugh A or B; total bilirubin less than or equal to the upper limit of normal (ULN) and AST greater than ULN, OR total bilirubin less than 3 times ULN with any AST): No dosage adjustment necessary.
    Severe hepatic impairment: Dose recommendations are not available.[60297]

    Renal Impairment

    Baseline Renal Impairment:
    Mild, moderate, or severe renal impairment (CrCL 15 to 89 mL/min): No dosage adjustment necessary.
    CrCL less than 15 mL/min or end stage renal disease (ESRD): Dose recommendations are not available.[60297]

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take with or without food.
    If a dose is missed, do not make up the missed dose. Take the next dose as scheduled.

    Extemporaneous Compounding-Oral

    For oral administration in patients who have difficulty swallowing solids:
    Disperse tablet in 2 ounces (approximately 60 mL) of non-carbonated water; do not mix with other liquids.
    Stir until tablet is dispersed into small pieces; it will not completely dissolve. Do not crush, heat, or ultrasonicate during preparation.
    Swallow immediately.
    Rinse the container with 4 to 8 ounces (120 mL to 240 mL) of water and immediately drink.
    For nasogastric (NG) tube administration:
    Disperse tablet in 15 mL of non-carbonated water; do not mix with other liquids.
    Stir until tablet is dispersed into small pieces; it will not completely dissolve. Do not crush, heat, or ultrasonicate during preparation.
    Use an additional 15 mL of water to transfer any residues to the syringe.
    Administer this 30 mL as per NG tube instructions with appropriate water flushes (approximately 30 mL).

    STORAGE

    Tagrisso:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis, pulmonary disease

    Use osimertinib with caution in patients with pre-existing pulmonary disease. Interstitial pulmonary disease/interstitial lung disease (ILD) or pneumonitis, including fatalities, have been reported with osimertinib therapy. Hold osimertinib therapy in patients who develop new or worsening pulmonary symptoms such as cough, dyspnea, fever, hypoxia, pleural effusion, or pulmonary infiltrates. Permanently discontinue therapy in patients with confirmed, treatment-related ILD or pneumonitis.

    Alcoholism, bradycardia, cardiac arrhythmias, coronary artery disease, diabetes mellitus, electrolyte imbalance, females, hepatic disease, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Prolongation of the heart rate-corrected QT (QTc) interval has occurred in patients treated with osimertinib; patients with a baseline QTc interval of 470 msec or greater were excluded from clinical trials. No QTc-related arrhythmias have been reported with osimertinib treatment. Use osimertinib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, cardiac failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalance. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. Periodically monitor ECGs and electrolytes of patients at increased risk. If the QTc interval is greater than 500 msec on 2 separate ECGs, withhold osimertinib therapy; a dose reduction may be necessary when the QTc decreases to less than 481 msec or baseline. Permanently discontinue therapy in patients with QTc prolongation and signs or symptoms of a life-threatening arrhythmia.

    Cardiac disease, cardiomyopathy, heart failure

    Cardiomyopathy, including heart failure, congestive heart failure, pulmonary edema, or decreased ejection fraction, has been reported with osimertinib therapy; some cases have been fatal. Patients with a history of cardiac disease may be at increased risk. In patients with cardiac risk factors, conduct cardiac monitoring including an assessment of the left ventricular ejection fraction (LVEF) before initiation of therapy and during treatment. Also assess the LVEF in patients who develop cardiac signs or symptoms during treatment. Permanently discontinue therapy for symptomatic congestive heart failure.

    Geriatric

    Monitor geriatric patients (older than 65 years) for an increased incidence of serious adverse reactions, as grade 3 and 4 adverse reactions occurred more often in this age group compared to patients younger than age 65 in an exploratory analysis (13.4% vs. 9.3%); more frequent dose modifications for adverse reactions (13.4% vs. 7.6%) also occurred.

    Keratitis, ocular inflammation, visual impairment

    Keratitis has been reported in patients treated with osimertinib in clinical trials. Promptly refer patients with signs and symptoms of keratitis (ocular inflammation, lacrimation, light sensitivity, visual impairment, eye pain, and/or red eye) to an ophthalmologist for evaluation.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, osimertinib can cause fetal harm if used by humans during pregnancy. When administered to pregnant rats prior to implantation through the end of organogenesis at exposures 1.5 times the exposure at the recommended human dose, post-implantation loss, embryolethality, and reduced fetal growth occurred. When administered to pregnant rats from implantation through the closure of the hard palate at exposures greater than or equal to 0.1 times the AUC observed in humans at the recommended dose, an equivocal increase in the rate of fetal malformations and variations was observed in treated litters compared to controls. In pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation day 6, an increase in total litter loss and postnatal death occurred. At a dose of 20 mg/kg/day, increased postnatal death and a slight reduction in mean pup weight at birth occurred.

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

    Counsel patients about the reproductive risk and contraception requirements during osimertinib treatment. Osimertinib can be teratogenic and embryotoxic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 6 weeks after treatment with osimertinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for 4 months after the last dose of osimertinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving osimertinib should be apprised of the potential hazard to the fetus. In addition, based on animal data, osimertinib may cause impaired fertility or infertility. The effects on female fertility showed a trend toward reversibility; it is not known whether the effects on male fertility are reversible. In male rats, degenerative changes were present in the testes of rats and dogs exposed to osimertinib for 1 month or more, with evidence of reversibility in the rat. Additionally, after 10 weeks of exposure to male rats at 0.5 times the AUC in humans at the recommended dose, increased pre-implantation loss occurred in untreated females. In repeat-dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries, and epithelial thinning in the uterus and vagina were seen in female rats after greater than or equal to 1 month of exposure at 0.3 times the AUC observed in humans at the recommended dose, with evidence of reversibility. In a female fertility study, rats treated at approximately 1.5 times the human Cmax at the recommended dose had no effects on cycling or becoming pregnant, but caused early embryonic deaths; these findings showed evidence of reversibility 1 month after treatment discontinuation.

    Breast-feeding

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

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 3.3-5.6
    cardiomyopathy / Delayed / 2.6-3.9
    neutropenia / Delayed / 2.2-3.0
    anorexia / Delayed / 1.1-2.5
    QT prolongation / Rapid / 0.9-2.2
    diarrhea / Early / 1.1-2.2
    hyponatremia / Delayed / 1.1-2.2
    pneumonitis / Delayed / 0-2.1
    asthenia / Delayed / 0.5-1.8
    fatigue / Early / 0.5-1.8
    hypermagnesemia / Delayed / 0.7-1.8
    hypokalemia / Delayed / 0.4-1.4
    rash / Early / 0.7-1.1
    elevated hepatic enzymes / Delayed / 0.7-1.1
    nausea / Early / 0.5-0.7
    stomatitis / Delayed / 0-0.7
    keratitis / Delayed / 0-0.7
    thrombocytopenia / Delayed / 0.7-0.7
    anemia / Delayed / 0-0.7
    dyspnea / Early / 0-0.4
    vomiting / Early / 0-0.4
    pruritus / Rapid / 0-0.4
    headache / Early / 0-0.4
    back pain / Delayed / 0-0.4
    cough / Delayed / 0-0.2
    constipation / Delayed / 0-0.2
    pulmonary embolism / Delayed / 1.8
    pulmonary edema / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    visual impairment / Early / Incidence not known

    Moderate

    hyperglycemia / Delayed / 20.0-37.0
    hyperbilirubinemia / Delayed / 14.0-14.0
    skin erosion / Delayed / Incidence not known
    erythema / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    fever / Early / 10.0-10.0
    infection / Delayed / 2.9-10.0
    xerosis / Delayed / 0-0.4
    folliculitis / Delayed / Incidence not known
    onycholysis / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    vesicular rash / Delayed / Incidence not known
    ocular pain / Early / Incidence not known
    lacrimation / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is a BCRP and P-glycoprotein (P-gp) substrate and osimertinib is a BCRP and P-gp inhibitor.
    Afatinib: (Moderate) If the concomitant use of osimertinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of osimertinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate. Osimertinib inhibits P-gp. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Albuterol: (Minor) Use osimertinib and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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) Use osimertinib and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 alfuzosin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Based on electrophysiology studies performed by the manufacturer, alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) If possible, avoid coadministration of amiodarone and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and 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. Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Amitriptyline: (Major) If possible, avoid coadministration of amitriptyline and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Amitriptyline; Chlordiazepoxide: (Major) If possible, avoid coadministration of amitriptyline and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of clarithromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Anagrelide: (Major) Do not use anagrelide with other drugs that prolong the QT interval. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects who received anagrelide.
    Apalutamide: (Major) Avoid coadministration of apalutamide with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If apalutamide is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Apomorphine: (Major) Avoid coadministration of apomorphine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Limited data indicate that QT prolongation is possible with apomorphine administration; however, the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Arformoterol: (Moderate) Use osimertinib and arformoterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as arformoterol as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Avoid coadministration of aripiprazole with osimertinib if possible due to the risk of QT prolongation and Torsade de Pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation such as osimertinib; discontinue osimertinib or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant use is unavoidable, frequently monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Concomitant use may increase the risk of QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid coadministration of artemether with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Artemether is also associated with prolongation of the QT interval. Concomitant use may increase the risk of QT prolongation. (Major) Avoid coadministration of lumefantrine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Artemether is also associated with prolongation of the QT interval. Concomitant use may increase the risk of QT prolongation.
    Asenapine: (Major) The manufacturer of asenapine recommends avoiding coadministration with other agents known to prolong the QT interval, such as osimertinib. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Asenapine has also been associated with QT prolongation. Concomitant use may increase the risk of QT prolongation.
    Atomoxetine: (Major) Avoid coadministration of atomoxetine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of phenobarbital with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If phenobarbital is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Azithromycin: (Major) Avoid coadministration of azithromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes if coadministration of azithromycin with osimertinib is necessary; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation and TdP have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Avoid coadministration of bedaquiline with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 phenobarbital with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If phenobarbital is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving osimertinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving osimertinib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; osimertinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3 fold.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of metronidazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of metronidazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Brentuximab vedotin: (Moderate) Monitor for brentuximab toxicities if given concurrently with osimertinib. Coadministration may increase the exposure of monomethyl auristatin E (MMAE), 1 of the 3 components released from brentuximab vedotin. Osimertinib is a P-gp inhibitor; brentuximab is a substrate for P-gp.
    Budesonide; Formoterol: (Moderate) Use osimertinib and formoterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as formoterol as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Avoid coadministration of buprenorphine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
    Buprenorphine; Naloxone: (Major) Avoid coadministration of buprenorphine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
    Carbamazepine: (Major) Avoid coadministration of carbamazepine with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If carbamazepine is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Ceritinib: (Major) Avoid coadministration of ceritinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in ceritinib-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes. An interruption of therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, and has also been reported with ceritinib. Additionally, ceritinib is a substrate of P-glycoprotein (P-gp) and osimertinib is a P-gp inhibitor.
    Chloroquine: (Major) Avoid coadministration of chloroquine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Chloroquine is associated with dose-dependent QT prolongation and TdP; fatalities have been reported.
    Chlorpromazine: (Major) Avoid coadministration of chlorpromazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP.
    Ciprofloxacin: (Major) Avoid coadministration of ciprofloxacin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsade de pointes (TdP), use of osimertinib with cisapride is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib. Concomitant use may increase the risk of QT prolongation.
    Citalopram: (Major) According to the manufacturer of citalopram, concurrent use with other medications that prolong the QT interval, such as osimertinib is not recommended. If coadministration is unavoidable, monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib; citalopram also causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Clomipramine: (Major) If possible, avoid coadministration of clomipramine and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Clozapine: (Major) Avoid coadministration of clozapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with osimertinib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of cobimetinib.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of promethazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Avoid coadministration of promethazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and osimertinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Osimertinib can inhibit colchicine's metabolism via P-glycoprotein (P-gp), resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken osimertinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Crizotinib: (Major) Avoid coadministration of crizotinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib; crizotinib has been associated with concentration-dependent QT prolongation.
    Cyclosporine: (Moderate) Monitor cyclosporine levels if coadministration with osimertinib is necessary; adjust the dose of cyclosporine if clinically appropriate. Cyclosporine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase cyclosporine exposure.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with osimertinib is necessary. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with osimertinib in patients with CrCL less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCL less than 30 mL/minute), avoid coadministration with osimertinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with osimertinib, a P-gp inhibitor; P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. Coadministration of dabigatran and a single oral dose of another P-gp inhibitor increased the dabigatran AUC and Cmax by 58% and 50%, respectively; there was additionally a 65% increase in renal clearance of dabigatran.
    Darunavir: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with osimertinib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate; osimertinib is a P-gp inhibitor. Coadministration with drugs that inhibit P-gp may decrease the clearance of darunavir, resulting in increased plasma concentrations.
    Darunavir; Cobicistat: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with osimertinib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate; osimertinib is a P-gp inhibitor. Coadministration with drugs that inhibit P-gp may decrease the clearance of darunavir, resulting in increased plasma concentrations.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with osimertinib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate; osimertinib is a P-gp inhibitor. Coadministration with drugs that inhibit P-gp may decrease the clearance of darunavir, resulting in increased plasma concentrations.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in dasabuvir-related adverse reactions during coadministration of osimertinib. Dasabuvir exposure may be increased. Dasabuvir is a substrate of BCRP and P-glycoprotein (P-gp). Osimertinib is a BCRP and P-gp inhibitor. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase plasma concentrations of ombitasvir. Ombitasvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase plasma concentrations of paritaprevir. Paritaprevir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Dasatinib: (Major) Avoid coadministration of dasatinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Degarelix: (Major) Avoid coadministration of degarelix with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QTc prolongation has also been reported with the use of degarelix.
    Desflurane: (Major) Avoid coadministration of halogenated anesthetics with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Major) If possible, avoid coadministration of desipramine and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Deutetrabenazine: (Major) Avoid coadministration of deutetrabenazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. If the patient is taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the deutetrabenazine dosage. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Clinically relevant QTc prolongation may also occur with deutetrabenazine.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of promethazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of quinidine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in quinidine-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Quinidine administration is associated with both QT prolongation and TdP. Additionally, quinidine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Disopyramide: (Major) Avoid coadministration of disopyramide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Disopyramide administration is associated with QT prolongation and TdP.
    Dofetilide: (Severe) Because of the potential for torsade de pointes (TdP), the use of osimertinib with dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Osimertinib causes concentration dependent prolongation of the QT interval at recommended dosing. Additive QT prolongation is possible.
    Dolasetron: (Major) Avoid coadministration of dolasetron with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is a BCRP and P-glycoprotein (P-gp) substrate and osimertinib is a BCRP and P-gp inhibitor.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of rilpivirine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is a BCRP and P-glycoprotein (P-gp) substrate and osimertinib is a BCRP and P-gp inhibitor.
    Donepezil: (Major) Avoid coadministration of donepezil with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Avoid coadministration of donepezil with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Doxepin: (Major) If possible, avoid coadministration of doxepin and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Doxorubicin: (Major) Avoid coadministration of osimertinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Osimertinib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronedarone: (Severe) Because of the potential for torsade de pointes (TdP), use of osimertinib with dronedarone is contraindicated. Dronedarone is associated with a risk for QT prolongation and TdP. Osimertinib causes concentration dependent prolongation of the QT interval at recommended dosing. Additive QT prolongation is possible.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as osimertinib. If coadministration cannot be avoided, use extreme caution; monitor electrolytes and ECGs for QT prolongation. Initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. An interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.
    Edoxaban: (Moderate) Monitor for an increase in edoxaban-related adverse reactions if coadministration with osimertinib is necessary. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism. Edoxaban is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use.
    Efavirenz: (Major) Avoid coadministration of efavirenz with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of efavirenz with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QTc prolongation has been observed with the use of efavirenz. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of efavirenz with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QTc prolongation has been observed with the use of efavirenz. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Eliglustat: (Major) Avoid coadministration of eliglustat with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of rilpivirine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of rilpivirine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Encorafenib: (Major) Avoid coadministration of encorafenib and osimertinib due to the potential for additive QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Encorafenib is associated with dose-dependent prolongation of the QT interval. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Enflurane: (Major) Avoid coadministration of halogenated anesthetics with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Halogenated anesthetics can also prolong the QT interval.
    Enzalutamide: (Major) Avoid coadministration of osimertinib with enzalutamide due to the risk of decreased osimertinib exposure, resulting in decreased efficacy. If concomitant use is unavoidable, increase the daily dose of osimertinib to 160 mg. Resume normal dosing of osimertinib (80 mg once daily) 3 weeks after discontinuation of enzalutamide. Osimertinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Eribulin: (Major) Avoid coadministration of eribulin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Avoid coadministration of erythromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Erythromycin is associated with QT prolongation and TdP.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of erythromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Erythromycin is associated with QT prolongation and TdP.
    Escitalopram: (Major) Avoid coadministration of escitalopram with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Escitalopram has been associated with a risk of QT prolongation and TdP.
    Ezogabine: (Major) Avoid coadministration of ezogabine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Ezogabine has also been associated with QT prolongation.
    Fingolimod: (Major) Avoid coadministration of fingolimod with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Fingolimod initiation results in decreased heart rate and may prolong the QT interval; after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 flecainide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or 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: (Major) Avoid coadministration of fluconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Fluconazole has been associated with QT prolongation and rare cases of TdP.
    Fluoxetine: (Major) Avoid coadministration of fluoxetine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of fluoxetine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation and TdP have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of olanzapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Use osimertinib and fluphenazine together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Fluphenazine is also 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) Use osimertinib and salmeterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as salmeterol as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with osimertinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold. (Moderate) Use osimertinib and vilanterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as vilanterol as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Use osimertinib and vilanterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as vilanterol as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) Avoid coadministration of fluvoxamine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation and TdP has been reported during fluvoxamine post-marketing use.
    Formoterol: (Moderate) Use osimertinib and formoterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as formoterol as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Use osimertinib and formoterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as formoterol as compared to short-acting beta-agonists.
    Foscarnet: (Major) Avoid the use of foscarnet with other drugs known to prolong the QT interval such as osimertinib. If concomitant use is necessary, periodically monitor ECGs and electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet; concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.
    Fosphenytoin: (Major) Avoid coadministration of fosphenytoin with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If fosphenytoin is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Gemifloxacin: (Major) Avoid coadministration of gemifloxacin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, obtain an ECG and serum electrolytes prior to the start of combination therapy, and periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and osimertinib as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Osimertinib is a BCRP and P-gp inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse reactions if coadministration with osimertinib is necessary. Pibrentasvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor. Concomitant use may increase plasma concentrations of pibrentasvir.
    Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, including hypoglycemia, if coadministration with osimertinib is necessary. Glyburide is a P-glycoprotein (P-gp) substrate. Osimertinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
    Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, including hypoglycemia, if coadministration with osimertinib is necessary. Glyburide is a P-glycoprotein (P-gp) substrate. Osimertinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
    Glycopyrrolate; Formoterol: (Moderate) Use osimertinib and formoterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as formoterol as compared to short-acting beta-agonists.
    Goserelin: (Major) Avoid coadministration of goserelin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Avoid coadministration of granisetron with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Granisetron has also been associated with QT prolongation.
    Halogenated Anesthetics: (Major) Avoid coadministration of halogenated anesthetics with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of haloperidol with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation and 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 halogenated anesthetics with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Halogenated anesthetics can also prolong the QT interval.
    Histrelin: (Major) Avoid coadministration of histrelin with osimertinib if possible due to the risk of QT prolongation and torsades de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes, correcting any electrolyte abnormalities; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Hydroxychloroquine: (Major) Hydroxychloroquine prolongs the QT interval and should not be administered with other drugs known to prolong the QT interval such as osimertinib. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Concomitant use may increase the risk of QT prolongation.
    Hydroxyzine: (Major) Avoid coadministration of hydroxyzine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
    Ibutilide: (Major) Avoid coadministration of ibutilide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Ibutilide administration can also cause QT prolongation and 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.
    Iloperidone: (Major) According to the manufacturer of iloperidone, coadministration with other agents known to prolong the QT interval, such as osimertinib, should be avoided. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, and iloperidone has also been associated with QT prolongation.
    Imatinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with osimertinib is necessary. Imatinib is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Imipramine: (Major) If possible, avoid coadministration of imipramine and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Indacaterol: (Moderate) Use osimertinib and indacaterol together with caution due to the risk of QT prolongation; monitor for an increase in indacaterol-related adverse reactions. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as indacaterol as compared to short-acting beta-agonists. Additionally, indacaterol is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Indacaterol; Glycopyrrolate: (Moderate) Use osimertinib and indacaterol together with caution due to the risk of QT prolongation; monitor for an increase in indacaterol-related adverse reactions. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as indacaterol as compared to short-acting beta-agonists. Additionally, indacaterol is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Indinavir: (Moderate) Monitor for an increase in indinavir-related adverse reactions if coadministration with osimertinib is necessary. Indinavir is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase indinavir exposure.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with osimertinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment; monitor electrolytes. An interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Inotuzumab has been associated with QT interval prolongation, and concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Irinotecan Liposomal: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with osimertinib is necessary. Irinotecan is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Irinotecan: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with osimertinib is necessary. Irinotecan is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Isoflurane: (Major) Avoid coadministration of halogenated anesthetics with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Halogenated anesthetics can also prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of rifampin with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If rifampin is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased osimertinib exposure by 78%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of rifampin with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If rifampin is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased osimertinib exposure by 78%.
    Itraconazole: (Major) Avoid coadministration of itraconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in itraconazole-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Itraconazole has also been associated with prolongation of the QT interval. Additionally, itraconazole is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with osimertinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib and/or osimertinib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Ketoconazole has also been associated with prolongation of the QT interval.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Lapatinib: (Major) Avoid coadministration of lapatinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in lapatinib-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Correct hypokalemia or hypomagnesemia prior to administration. Lapatinib is a P-glycoprotein (P-gp) substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
    Ledipasvir; Sofosbuvir: (Moderate) Monitor for an increase in sofosbuvir-related adverse reactions if coadministration with osimertinib is necessary. Sofosbuvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with osimertinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Leuprolide: (Major) Avoid coadministration of leuprolide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (Minor) Use osimertinib and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 levofloxacin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Levofloxacin has been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Major) Avoid coadministration of lithium with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of lofexidine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Loperamide: (Major) Avoid coadministration of loperamide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Also, closely monitor for an increase in loperamide-related adverse reactions, including CNS effects and cardiac effects (e.g., syncope, ventricular tachycardia, cardiac arrest). Loperamide is a P-glycoprotein (P-gp) substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, which is also a P-gp inhibitor.
    Loperamide; Simethicone: (Major) Avoid coadministration of loperamide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Also, closely monitor for an increase in loperamide-related adverse reactions, including CNS effects and cardiac effects (e.g., syncope, ventricular tachycardia, cardiac arrest). Loperamide is a P-glycoprotein (P-gp) substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, which is also a P-gp inhibitor.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Lopinavir is associated with QT prolongation; additive QT prolongation may occur.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If lumacaftor; ivacaftor is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If lumacaftor; ivacaftor is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as osimertinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Maprotiline: (Major) Avoid coadministration of maprotiline with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with osimertinib is necessary. Maraviroc is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase maraviroc exposure.
    Mefloquine: (Major) Avoid coadministration of mefloquine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for increased mefloquine-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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. Additionally, mefloquine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Meperidine; Promethazine: (Major) Avoid coadministration of promethazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Mephobarbital: (Major) Avoid coadministration of mephobarbital with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If mephobarbital is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Metaproterenol: (Minor) Use osimertinib and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 methadone with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, use extreme caution; monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methotrexate: (Moderate) Monitor for an increase in methotrexate-related adverse reactions if coadministration with osimertinib is necessary. Methotrexate is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Metronidazole: (Major) Avoid coadministration of metronidazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Avoid coadministration of midostaurin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation was also reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Avoid coadministration of mifepristone with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Mifepristone has also been associated with dose-dependent prolongation of the QT interval.
    Mirtazapine: (Major) Avoid coadministration of mirtazapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Mirtazapine has also been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing surveillance with mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid coadministration of mitotane with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If mitotane is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Mitoxantrone: (Moderate) Monitor for an increase in mitoxantrone-related adverse reactions if coadministration with osimertinib is necessary. Mitoxantrone is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death, if coadministration with osimertinib is necessary; decrease the dose of morphine as clinically appropriate. Morphine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. The concomitant use of P-gp inhibitors can increase the exposure to morphine by about 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death, if coadministration with osimertinib is necessary; decrease the dose of morphine as clinically appropriate. Morphine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. The concomitant use of P-gp inhibitors can increase the exposure to morphine by about 2-fold.
    Moxifloxacin: (Major) Avoid coadministration of moxifloxacin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Naldemedine: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with osimertinib is necessary. Naldemedine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase naldemedine exposure.
    Nelfinavir: (Moderate) Monitor for an increase in nelfinavir-related adverse reactions if coadministration with osimertinib is necessary. Nelfinavir is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase nelfinavir exposure.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and osimertinib; significant prolongation of the QT interval may occur. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Norfloxacin: (Major) Avoid coadministration of norfloxacin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Quinolones have been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) If possible, avoid coadministration of nortriptyline and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Octreotide: (Major) Avoid coadministration of octreotide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Avoid coadministration of ofloxacin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Quinolones have been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Avoid coadministration of olanzapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Use osimertinib and olodaterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as olodaterol as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase plasma concentrations of ombitasvir. Ombitasvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase plasma concentrations of paritaprevir. Paritaprevir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Ondansetron: (Major) Avoid coadministration of ondansetron with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, correct electrolyte abnormalities prior to administration of oxaliplatin. Periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation and ventricular arrhythmias including fatal TdP 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) According to the manufacturer of paliperidone, coadministration with other agents that prolong the QT interval, such as osimertinib, should be avoided. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, and paliperidone has also been associated with QT prolongation.
    Panobinostat: (Major) According to the manufacturer of panobinostat, coadministration with other agents that prolong the QT interval, such as osimertinib, is not recommended. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, and QT prolongation has also been reported with panobinostat. Additionally, panobinostat is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor; concomitant use may increase panobinostat exposure.
    Pasireotide: (Major) Avoid coadministration of pasireotide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation has also occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) According to the manufacturer of pazopanib, coadministration with other medications that prolong the QT interval, such as osimertinib, is not advised. If concomitant use is unavoidable, monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Additionally, monitor for an increase in pazopanib related adverse reactions if coadministration with osimertinib is necessary. Pazopanib is a BCRP and P-glycoprotein (P-gp) substrate that has been reported to prolong the QT interval. Osimertinib is a BCRP and P-gp inhibitor that is associated with concentration-dependent QT prolongation.
    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 pentamidine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Systemic pentamidine has also been associated with QT prolongation.
    Perphenazine: (Minor) Use osimertinib and perphenazine together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Major) If possible, avoid coadministration of amitriptyline and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. (Minor) Use osimertinib and perphenazine together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) Avoid coadministration of phenobarbital with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If phenobarbital is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of promethazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of phenytoin with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If phenytoin is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Pimavanserin: (Major) Avoid coadministration of pimavanserin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is necessary, periodically monitor ECGs and electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Pimavanserin may also cause QT prolongation.
    Pimozide: (Severe) Concomitant use of osimertinib and pimozide is contraindicated because there is an increased risk of QT prolongation and torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. Osimertinib causes concentration dependent prolongation of the QT interval at recommended dosing.
    Pirbuterol: (Minor) Use osimertinib and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Posaconazole: (Major) Avoid coadministration of posaconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in posaconazole-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Posaconazole is a P-glycoprotein (P-gp) substrate that has been associated with prolongation of the QT interval as well as rare cases of TdP. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, which is also a P-gp inhibitor.
    Primaquine: (Major) Avoid coadministration of primaquine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Primaquine may also cause QT interval prolongation.
    Primidone: (Major) Avoid coadministration of primidone with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If primidone is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Procainamide: (Major) Avoid coadministration of procainamide with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Procainamide is associated with a well-established risk of QT prolongation and TdP.
    Prochlorperazine: (Minor) Use osimertinib and prochlorperazine together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 promethazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of propafenone with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Propafenone is a Class IC antiarrhythmic which increases the QT interval, largely due to prolongation of the QRS interval.
    Protriptyline: (Major) If possible, avoid coadministration of protriptyline and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Quetiapine: (Major) Avoid coadministration of quetiapine with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is necessary, periodically monitor ECGs and electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.
    Quinidine: (Major) Avoid coadministration of quinidine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in quinidine-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Quinidine administration is associated with both QT prolongation and TdP. Additionally, quinidine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Quinine: (Major) Avoid coadministration of quinine with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for an increase in quinine-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Quinine is a P-glycoprotein (P-gp) substrate that has been associated with QT prolongation and rare cases of TdP. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, which is also a P-gp inhibitor.
    Ranolazine: (Major) Avoid coadministration of ranolazine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in ranolazine-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Ranolazine is a P-glycoprotein (P-gp) substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration may result in additive QT prolongation. Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
    Ribociclib: (Major) Avoid coadministration of ribociclib with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. For ribociclib, these ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). Both drugs have been shown to prolong the QT interval in a concentration-dependent manner. For ribociclib, these ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Rifampin: (Major) Avoid coadministration of rifampin with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If rifampin is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased osimertinib exposure by 78%.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with osimertinib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Rilpivirine: (Major) Avoid coadministration of rilpivirine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Risperidone: (Major) Avoid coadministration of risperidone with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in risperidone-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Additionally, risperidone is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Romidepsin: (Major) Avoid coadministration of romidepsin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in romidepsin-related adverse reactions, monitor electrolytes, and monitor ECGs for QT prolongation at baseline and periodically during treatment; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Romidepsin is a P-glycoprotein (P-gp) substrate that has been reported to prolong the QT interval. Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
    Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including rhabdomyolysis and myopathy, if coadministration with osimertinib is necessary. Rosuvastatin is a BCRP substrate and osimertinib is a BCRP inhibitor. Concomitant use increased the AUC of rosuvastatin by 35% and the Cmax by 72%.
    Salmeterol: (Moderate) Use osimertinib and salmeterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as salmeterol as compared to short-acting beta-agonists.
    Saquinavir: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as osimertinib. If concomitant use is unavoidable, monitor for an increase in saquinavir-related adverse reactions, monitor electrolytes, and monitor ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Saquinavir is a P-glycoprotein (P-gp) substrate that, when boosted with ritonavir, increases the QT interval in a dose-dependent fashion which may increase the risk for serious arrhythmias such as TdP. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
    Sertraline: (Major) Avoid coadministration of sertraline with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline.
    Sevoflurane: (Major) Avoid coadministration of halogenated anesthetics with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Use osimertinib and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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.
    Simeprevir: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with osimertinib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase simeprevir exposure.
    Sirolimus: (Moderate) Monitor for an increase in sirolimus-related adverse reactions if coadministration with osimertinib is necessary. Monitor sirolimus concentrations and adjust the dose as clinically appropriate. Sirolimus is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Sofosbuvir: (Moderate) Monitor for an increase in sofosbuvir-related adverse reactions if coadministration with osimertinib is necessary. Sofosbuvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in sofosbuvir-related adverse reactions if coadministration with osimertinib is necessary. Sofosbuvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in sofosbuvir-related adverse reactions if coadministration with osimertinib is necessary. Sofosbuvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Solifenacin: (Major) Avoid coadministration of solifenacin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Solifenacin has also been associated with dose-dependent prolongation of the QT interval; TdP has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Avoid coadministration of sorafenib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Avoid coadministration of sotalol with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Sotalol administration is associated with QT prolongation and 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 St. John's Wort with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If St. John's Wort is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer, although the effect varies widely and is preparation-dependent. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Sulfasalazine: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with osimertinib is necessary. Sulfasalazine is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Sunitinib: (Major) Avoid coadministration of sunitinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Sunitinib can also prolong the QT interval.
    Tacrolimus: (Major) Avoid coadministration of tacrolimus with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tacrolimus also causes QT prolongation.
    Talazoparib: (Major) Avoid coadministration of osimertinib with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and osimertinib is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Major) Avoid coadministration of telavancin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Telavancin has also been associated with QT prolongation.
    Telithromycin: (Major) Avoid coadministration of telithromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Telithromycin is associated with QT prolongation and TdP.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with osimertinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir alafenamide is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
    Terbutaline: (Minor) Use osimertinib and short-acting beta-agonists together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is necessary, periodically monitor ECGs and electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.
    Thioridazine: (Severe) Concomitant use of osimertinib and thioridazine is contraindicated because there is an increased risk of QT prolongation and torsade de pointes (TdP). Osimertinib causes concentration dependent prolongation of the QT interval at recommended dosing. In addition, thioridazine is associated with a well-established risk of QT prolongation and TdP. Coadministration may further increase the risk of QT prolongation.
    Ticagrelor: (Moderate) Monitor for an increase in ticagrelor-related adverse reactions, including bleeding, if coadministration with osimertinib is necessary. Ticagrelor is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Tiotropium; Olodaterol: (Moderate) Use osimertinib and olodaterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as olodaterol as compared to short-acting beta-agonists.
    Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with osimertinib is necessary. Tipranavir is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Tolterodine: (Major) Avoid coadministration of tolterodine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Tolvaptan: (Moderate) Coadministration of tolvaptan and osimertinib may result in increased plasma concentrations of tolvaptan. Monitor patients closely for tolvaptan-related adverse effects including a rise in serum sodium concentrations, polyuria, thirst, and dehydration. The dose of tolvaptan may need to be reduced. Tolvaptan is a P-glycoprotein (P-gp) substrate; osimertinib is a P-gp inhibitor.
    Topotecan: (Major) Avoid coadministration of osimertinib with oral topotecan due to increased topotecan exposure; osimertinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); osimertinib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Toremifene: (Major) Avoid coadministration of osimertinib with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner
    Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with osimertinib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase verapamil exposure.
    Trazodone: (Major) Avoid coadministration of trazodone with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is necessary, periodically monitor ECGs and electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.
    Trifluoperazine: (Minor) Use osimertinib and trifluoperazine together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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) If possible, avoid coadministration of trimipramine and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Triptorelin: (Major) Avoid coadministration of triptorelin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Umeclidinium: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with osimertinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with osimertinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold. (Moderate) Use osimertinib and vilanterol together with caution due to the risk of QT prolongation. The manufacturer of osimertinib recommends avoiding coadministration with other drugs that prolong the QT, if possible; if unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes. An interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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 such as vilanterol as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with vandetanib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor electrolytes and ECGs for QT prolongation; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of therapy or dose reduction for both drugs may be necessary for QT prolongation. Both osimertinib and vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have also been reported in patients receiving vandetanib.
    Vardenafil: (Major) Avoid coadministration of vardenafil with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Vardenafil is associated with QTc prolongation at both therapeutic and supratherapeutic doses.
    Vemurafenib: (Major) Avoid coadministration of vemurafenib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Vemurafenib has also been associated with QT prolongation.
    Venetoclax: (Major) Avoid coadministration of venetoclax with osimertinib if possible; consider alternative treatments. If concomitant use is unavoidable, consider reducing the venetoclax dose by at least 50% and monitor closely for venetoclax-related adverse reactions. Resume the venetoclax dose that was used prior to initiating treatment with osimertinib 2 to 3 days after discontinuation of osimertinib. Osimertinib is a P-glycoprotein (P-gp) inhibitor and venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78%.
    Venlafaxine: (Major) Avoid coadministration of venlafaxine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with osimertinib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase verapamil exposure.
    Vincristine Liposomal: (Moderate) Monitor for an increase in vincristine-related adverse reactions if coadministration with osimertinib is necessary. Vincristine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Vincristine: (Moderate) Monitor for an increase in vincristine-related adverse reactions if coadministration with osimertinib is necessary. Vincristine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Voriconazole: (Major) Avoid coadministration of voriconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Voriconazole has also been associated with QT prolongation and rare cases of TdP.
    Vorinostat: (Major) Avoid coadministration of vorinostat with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Vorinostat therapy is also associated with a risk of QT prolongation.
    Ziprasidone: (Major) Concomitant use of ziprasidone and osimertinib 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. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, osimertinib can cause fetal harm if used by humans during pregnancy. When administered to pregnant rats prior to implantation through the end of organogenesis at exposures 1.5 times the exposure at the recommended human dose, post-implantation loss, embryolethality, and reduced fetal growth occurred. When administered to pregnant rats from implantation through the closure of the hard palate at exposures greater than or equal to 0.1 times the AUC observed in humans at the recommended dose, an equivocal increase in the rate of fetal malformations and variations was observed in treated litters compared to controls. In pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation day 6, an increase in total litter loss and postnatal death occurred. At a dose of 20 mg/kg/day, increased postnatal death and a slight reduction in mean pup weight at birth occurred.

    Counsel patients about the reproductive risk and contraception requirements during osimertinib treatment. Osimertinib can be teratogenic and embryotoxic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 6 weeks after treatment with osimertinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for 4 months after the last dose of osimertinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving osimertinib should be apprised of the potential hazard to the fetus. In addition, based on animal data, osimertinib may cause impaired fertility or infertility. The effects on female fertility showed a trend toward reversibility; it is not known whether the effects on male fertility are reversible. In male rats, degenerative changes were present in the testes of rats and dogs exposed to osimertinib for 1 month or more, with evidence of reversibility in the rat. Additionally, after 10 weeks of exposure to male rats at 0.5 times the AUC in humans at the recommended dose, increased pre-implantation loss occurred in untreated females. In repeat-dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries, and epithelial thinning in the uterus and vagina were seen in female rats after greater than or equal to 1 month of exposure at 0.3 times the AUC observed in humans at the recommended dose, with evidence of reversibility. In a female fertility study, rats treated at approximately 1.5 times the human Cmax at the recommended dose had no effects on cycling or becoming pregnant, but caused early embryonic deaths; these findings showed evidence of reversibility 1 month after treatment discontinuation.

    MECHANISM OF ACTION

    Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR), irreversibly binding to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at concentrations that are approximately 9-fold lower than for wild-type EGFR. In cultured cells and animal models, it has shown NSCLC anti-tumor activity against the following EGFR mutations: T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion; to a lesser extent, it has shown activity against wild-type EGFR amplifications. The active metabolite AZ7550 has similar potency to osimertinib, while AZ5104 has approximately 8-fold greater potency against exon 19 deletion and T790M mutations and approximately 15-fold greater potency against wild-type EGFR. In vitro, osimertinib also inhibits HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations.

    PHARMACOKINETICS

    Osimertinib is administered orally and exhibits linear pharmacokinetics. The mean volume of distribution (Vd/F) at steady-state was 918 liters; plasma protein binding was 95%. The mean estimated half-life of osimertinib is 48 hours, and clearance (CL/F) is 14.3 L/hour. Once daily administration results in approximately 3-fold accumulation, with steady-state achieved after 15 days of dosing. Osimertinib is primarily excreted in the feces (68%) and to a lesser extent in the urine (14%); unchanged drug accounts for approximately 2% of elimination.
     
    Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A, CYP1A2, P-glycoprotein (P-gp), BCRP
    The main metabolic pathways of osimertinib are oxidation, predominately via CYP3A, and dealkylation in vitro. Osimertinib has two pharmacologically active metabolites in the plasma, AZ7550 and AZ5104. AZ7550 has similar potency to osimertinib, while AZ5104 showed approximately 8-fold greater potency against exon 19 deletion and T790M mutations, and approximately 15-fold greater potency against wild-type EGFR. The geometric mean exposure (AUC) of each metabolite was approximately 10% of the exposure of osimertinib at steady state. Avoid coadministration with strong CYP3A4 inducers, or increase the dose of osimertinib if concomitant use is unavoidable. Precautions or dose adjustments are not necessary with CYP3A4 inhibitors. Osimertinib inhibits P-gp and BCRP, and may affect plasma concentrations of substrates of these transporters. Coadministration with rosuvastatin (a BCRP substrate) increased the rosuvastatin AUC by 35% and Cmax by 72%. Coadministration with fexofenadine (a P-gp substrate) increased the fexofenadine AUC and Cmax by 56% and 76% after a single dose and 27% and 25% at steady state, respectively. In vitro, osimertinib is also a P-gp and BCRP substrate as well as a BCRP inhibitor and CYP1A2 inducer.[60297]

    Oral Route

    The AUC and Cmax of osimertinib increases in a dose-proportional manner over 20 mg to 240 mg (0.25 to 3 times the recommended dose). At steady-state, the Cmax to Cmin ratio was 1.6-fold. The median time to Cmax of osimertinib was 6 hours (range, 3 to 24 hours). The Cmax and AUC of osimertinib after administration of a high-fat, high-calorie meal (approximately 1,000 calories and 58 grams of fat) was comparable to under fasting conditions.