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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    An oral EGFR kinase inhibitor
    Used for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy
    Serious adverse effects include QTc prolongation, neutropenia, ILD/pneumonitis and cerebrovascular accident

    COMMON BRAND NAMES

    Tagrisso

    HOW SUPPLIED

    Tagrisso Oral Tab: 40mg, 80mg

    DOSAGE & INDICATIONS

    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. 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 were randomized to receive osimertinib (n = 279) or pemetrexed plus carboplatin or cisplatin (n = 140); maintenance pemetrexed was allowed. The primary endpoint of median progression-free survival (PFS) was significantly longer in the osimertinib arm (10.1 vs. 4.4 months; HR 0.3; p < 0.001); the benefit of osimertinib on PFS was consistent among patients with CNS metastases (n = 144) (8.5 vs. 4.2 months; HR 0.32; 95% CI, 0.21 to 0.49). The objective response rate was also significantly better with osimertinib compared with pemetrexed plus platinum therapy (71% vs. 31%; odds ratio, 5.39; p < 0.001). Data for overall survival were not yet mature.

    MAXIMUM DOSAGE

    Adults

    80 mg by mouth once daily; 160 mg once daily when used with a strong CYP3A4 inducer.

    Geriatric

    80 mg by mouth once daily; 160 mg once daily when used with a strong CYP3A4 inducer.

    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 (total bilirubin less than or equal to the upper limit of normal (ULN) and AST 1 to 1.5 times ULN OR total bilirubin less than 3 times ULN with any AST): No dosage adjustment necessary.
    Severe hepatic impairment: Dose recommendations are not available.
    Treatment-Related Hepatotoxicity:
    Grade 3 or higher hepatotoxicity (total bilirubin greater than 3 times ULN or AST/ALT > 5 times ULN): Hold osimertinib therapy. Resume treatment at 40 mg or 80 mg once daily if liver function tests improve to grade 0 to 2 within 3 weeks. Permanently discontinue therapy if there is no improvement within 3 weeks.

    Renal Impairment

    Baseline Renal Impairment:
    Mild, moderate, or severe renal impairment (CrCL 15 to 89 mL/min): No dosage adjustment necessary.
    CrCl < 15 ml/min or end stage renal disease (ESRD): Dose recommendations are not available.
     
    Treatment-Related Nephrotoxicity:
    Grade 3 or higher nephrotoxicity (SCr greater than 3 times the upper limit of normal (ULN) or CrCL less than 25% of the lower limit of normal (LLN)): Hold osimertinib therapy. Resume treatment at 40 mg or 80 mg once daily if renal function improves to grade 0 to 2 within 3 weeks. Permanently discontinue therapy if there is no improvement within 3 weeks.

    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

    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 or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks.

    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 (9.8% vs. 6.8%); more frequent dose modifications for adverse reactions (10.1% vs. 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, 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 >= 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

    neutropenia / Delayed / 3.4-3.4
    hyponatremia / Delayed / 3.4-3.4
    lymphopenia / Delayed / 3.3-3.3
    stroke / Early / 2.7-2.7
    thromboembolism / Delayed / 2.4-2.4
    cardiomyopathy / Delayed / 1.4-1.4
    thrombocytopenia / Delayed / 1.2-1.2
    pneumonitis / Delayed / 0.5-1.0
    diarrhea / Early / 1.0-1.0
    anorexia / Delayed / 0.7-0.7
    back pain / Delayed / 0.7-0.7
    hypermagnesemia / Delayed / 0.7-0.7
    nausea / Early / 0.5-0.5
    rash (unspecified) / Early / 0.5-0.5
    fatigue / Early / 0.5-0.5
    cough / Delayed / 0.2-0.2
    constipation / Delayed / 0.2-0.2
    headache / Early / 0.2-0.2
    anemia / Delayed / 0.2-0.2
    pulmonary embolism / Delayed / 2.0
    pulmonary edema / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    keratitis / Delayed / Incidence not known

    Moderate

    stomatitis / Delayed / 12.0-12.0
    QT prolongation / Rapid / 0.2-2.7
    thrombosis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    blepharitis / Early / Incidence not known
    cataracts / Delayed / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    xerosis / Delayed / 31.0-31.0
    pruritus / Rapid / 14.0-14.0
    onycholysis / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    lacrimation / Early / Incidence not known
    ocular pain / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    ocular irritation / Rapid / 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 substrate and osimertinib is a BCRP inhibitor.
    Albuterol: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of short-acting beta-agonists such as albuterol and levalbuterol with osimertinib is necessary; 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. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of short-acting beta-agonists such as albuterol and levalbuterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of alfuzosin with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of amitriptyline with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of amitriptyline with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of clarithromycin with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of clarithromycin with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Anagrelide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of anagrelide with osimertinib is necessary; 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. Ventricular tachycardia and torsade de pointes (TdP) have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Apomorphine: (Major) Periodically monitor ECGs and electrolytes if coadministration of osimertinib with apomorphine is necessary due to the risk of QT prolongation and torsade de pointes (TdP); 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. Limited data indicate that QT prolongation is also possible with apomorphine administration; however, the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. Concomitant use may increase the risk of QT prolongation.
    Arformoterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of arformoterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of aripiprazole with osimertinib is necessary; 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. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole as well as 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of atomoxetine with osimertinib is necessary; 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; QT prolongation has also occurred during therapeutic use of atomoxetine as well as 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of azithromycin with osimertinib is necessary; 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. Both QT prolongation and TdP have been spontaneously reported with azithromycin use in postmarketing surveillance.
    Bedaquiline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of bedaquiline with osimertinib is necessary; 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. Bedaquiline has also 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%.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of metronidazole with osimertinib is necessary; 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. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of metronidazole with osimertinib is necessary; 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. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Budesonide; Formoterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of formoterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of buprenorphine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. The FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP, and concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    Buprenorphine; Naloxone: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of buprenorphine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. The FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP, and concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
    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) Monitor electrolytes and ECGs for QT prolongation in patients receiving concomitant treatment with ceritinib and osimertinib; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for both drugs if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Concentration-dependent QTc prolongation has occurred in clinical trials with both ceritinib and osimertinib.
    Chloroquine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of chloroquine with osimertinib is necessary; 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. Chloroquine is additionally associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is also increased with higher chloroquine doses.
    Chlorpromazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of chlorpromazine with osimertinib is necessary; 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. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ciprofloxacin with osimertinib is necessary; 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. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsade de pointes (TdP), use of 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of clarithromycin with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Clomipramine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of clomipramine with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of clozapine with osimertinib is necessary; 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. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (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 substrate and osimertinib is a BCRP inhibitor.
    Codeine; Phenylephrine; Promethazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of promethazine with osimertinib is necessary; 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. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of promethazine with osimertinib is necessary; 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. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with osimertinib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Concentration-dependent QTc prolongation has been suggested at the recommended dosing of osimertinib in a pharmacokinetic/pharmacodynamic analysis. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Cyclobenzaprine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of cyclobenzaprine with osimertinib is necessary; 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. Cyclobenzaprine is associated with a possible risk of QT prolongation and torsade de pointes (TdP), particularly in the event of acute overdose.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ritonavir with osimertinib is necessary; 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; the use of ritonavir could also result in QT prolongation. (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. Osimertinib is a BCRP 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 substrate and osimertinib is a BCRP 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 substrate and osimertinib is a BCRP inhibitor.
    Dasatinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of dasatinib with osimertinib is necessary; 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. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Daunorubicin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of daunorubicin with osimertinib is necessary; 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. Acute cardiotoxicity can occur during the administration of daunorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    Degarelix: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of degarelix with osimertinib is necessary; 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 QTc prolongation has also been reported with the use of degarelix.
    Desflurane: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with osimertinib is necessary; 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; halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of desipramine with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of deutetrabenazine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. For patients taking a deutetrabenazine dosage more than 24 mg/day with osimertinib, assess the QTc interval before and after increasing the dosage of either medication. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Clinically relevant QTc prolongation may also occur with deutetrabenazine.
    Dextromethorphan; Promethazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of promethazine with osimertinib is necessary; 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. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of quinidine with osimertinib is necessary; 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. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
    Disopyramide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of disopyramide with osimertinib is necessary; 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. Disopyramide administration is also associated with QT prolongation and torsade de pointes (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) Monitor electrolytes and ECGs for QT prolongation if coadministration of dolasetron with osimertinib is necessary; 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. Dolasetron has also been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Donepezil: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of donepezil with osimertinib is necessary; 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. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Donepezil; Memantine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of donepezil with osimertinib is necessary; 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. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Doxepin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of doxepin with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Doxorubicin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of doxorubicin with osimertinib is necessary; 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. Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    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.
    Efavirenz: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of efavirenz with osimertinib is necessary; 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 QTc prolongation has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of efavirenz with osimertinib is necessary; 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 QTc prolongation has also 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 substrate and osimertinib is a BCRP inhibitor.
    Eliglustat: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of eliglustat with osimertinib is necessary; 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. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of rilpivirine with osimertinib is necessary; 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of rilpivirine with osimertinib is necessary; 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. 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 substrate and osimertinib is a BCRP 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 substrate and osimertinib is a BCRP inhibitor.
    Enflurane: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with osimertinib is necessary; 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; 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%.
    Epirubicin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of epirubicin with osimertinib is necessary; 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. Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    Eribulin: (Major) Closely monitor electrolytes and ECGs for QT prolongation if coadministration of osimertinib with eribulin is necessary; 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 eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of erythromycin with osimertinib is necessary; 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. Erythromycin is also associated with QT prolongation as well as torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of erythromycin with osimertinib is necessary; 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. Erythromycin is also associated with QT prolongation as well as torsade de pointes (TdP).
    Escitalopram: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of escitalopram with osimertinib is necessary; 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. Escitalopram has also been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Ezogabine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ezogabine with osimertinib is necessary; 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 ezogabine has been associated with QT prolongation.
    Fingolimod: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of fingolimod with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction 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 torsade de pointes (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) Monitor electrolytes and ECGs for QT prolongation if coadministration of flecainide with osimertinib is necessary; 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. Flecainide is a Class IC antiarrhythmic that increases the QT interval, largely due to prolongation of the QRS interval. Although causality for torsade de pointes (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 including TdP.
    Fluconazole: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of fluconazole with osimertinib is necessary; 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. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Fluoxetine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of fluoxetine with osimertinib is necessary; 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; QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of fluoxetine with osimertinib is necessary; 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; QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine. (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of olanzapine with osimertinib is necessary; 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. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of fluphenazine with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of salmeterol with osimertinib is necessary; 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. Beta-agonists may also 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 electrolytes and ECGs for QT prolongation if coadministration of vilanterol with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of vilanterol with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of fluvoxamine with osimertinib is necessary; 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; QT prolongation and torsade de pointes (TdP) has also been reported during fluvoxamine post-marketing use.
    Formoterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of formoterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of formoterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of gemifloxacin with osimertinib is necessary; 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. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of gemtuzumab with osimertinib is necessary; 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. 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); osimertinib is an inhibitor of BCRP. (Moderate) Monitor for an increase in pibrentasvir-related adverse reactions if coadministration with osimertinib is necessary. Pibrentasvir is a BCRP substrate and osimertinib is a BCRP inhibitor; concomitant use may increase plasma concentrations of pibrentasvir.
    Glycopyrrolate; Formoterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of formoterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of goserelin with osimertinib is necessary; 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. Androgen deprivation therapy (e.g., goserelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of granisetron with osimertinib is necessary; 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 granisetron has also been associated with QT prolongation.
    Halogenated Anesthetics: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with osimertinib is necessary; 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; halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of haloperidol with osimertinib is necessary; 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. QT prolongation and torsade de pointes (TdP) have also been observed during haloperidol treatment; excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk.
    Halothane: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with osimertinib is necessary; 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; halogenated anesthetics can also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of hydroxyzine with osimertinib is necessary; 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; postmarketing data indicate that hydroxyzine also causes QT prolongation and torsade de pointes (TdP).
    Ibutilide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ibutilide with osimertinib is necessary; 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. Ibutilide administration can also cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated.
    Idarubicin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of idarubicin with osimertinib is necessary; 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. Acute cardiotoxicity can occur during the administration of idarubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    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) Monitor electrolytes and ECGs for QT prolongation if coadministration of imipramine with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of indacaterol with osimertinib is necessary; 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. Beta-agonists may also 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.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of indacaterol with osimertinib is necessary; 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. Beta-agonists may also 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.
    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: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with osimertinib is necessary. Irinotecan is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Isoflurane: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with osimertinib is necessary; 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; 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of itraconazole with osimertinib is necessary; 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. Itraconazole has also been associated with prolongation of the QT interval.
    Ketoconazole: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ketoconazole with osimertinib is necessary; 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. Ketoconazole has also been associated with prolongation of the QT interval.
    Lapatinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of lapatinib with osimertinib is necessary; correct hypokalemia or hypomagnesemia prior to administration. An interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Both drugs have been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lenvatinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of lenvatinib with osimertinib is necessary; 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; QT prolongation was also reported during clinical trials of lenvatinib.
    Leuprolide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of leuprolide with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of leuprolide with osimertinib is necessary; 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. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of short-acting beta-agonists such as albuterol and levalbuterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of levofloxacin with osimertinib is necessary; 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. Levofloxacin has been associated with a risk of QT prolongation. although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of lithium with osimertinib is necessary; 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; lithium has also been associated with QT prolongation.
    Loperamide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of loperamide with osimertinib is necessary; 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of loperamide with osimertinib is necessary; 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of lopinavir with osimertinib is necessary; 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 lopinavir; ritonavir is associated with QT prolongation. Concomitant use may result in additive QT prolongation. (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ritonavir with osimertinib is necessary; 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; the use of ritonavir could also result in QT prolongation.
    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%.
    Maprotiline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of maprotiline with osimertinib is necessary; 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. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of mefloquine with osimertinib is necessary; 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. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine; Promethazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of promethazine with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of short-acting beta-agonists such as albuterol and levalbuterol with osimertinib is necessary; 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. Beta-agonists may also 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) Methadone should only be coadministered with osimertinib under extreme caution and after a careful assessment of treatment risks versus benefits, due to the risk of QT prolongation. Monitor electrolytes and ECGs for QT prolongation if concomitant use is necessary; 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. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    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) Monitor electrolytes and ECGs for QT prolongation if coadministration of metronidazole with osimertinib is necessary; 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. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of midostaurin with osimertinib is necessary; 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; QT prolongation was also reported in patients who received midostaurin in clinical trials.
    Mifepristone, RU-486: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of mifepristone with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Both drugs have been associated with concentration-dependent QTc prolongation.
    Mirtazapine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of mirtazapine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Both drugs have been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience 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.
    Moxifloxacin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of moxifloxacin with osimertinib is necessary; 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. Quinolones have also been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nilotinib: (Major) Avoid coadministration of nilotinib with osimertinib due to the risk of 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. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib; nilotinib has also been associated with QT prolongation.
    Nortriptyline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of nortriptyline with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of octreotide with osimertinib is necessary; 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. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ofloxacin with osimertinib is necessary; 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. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of olanzapine with osimertinib is necessary; 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. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of olodaterol with osimertinib is necessary; 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. Beta-agonists may also 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: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ritonavir with osimertinib is necessary; 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; the use of ritonavir could also result in QT prolongation. (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 substrate and osimertinib is a BCRP 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 substrate and osimertinib is a BCRP inhibitor.
    Ondansetron: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ondansetron with osimertinib is necessary; 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. Ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of oxaliplatin with osimertinib is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. 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. QT prolongation and ventricular arrhythmias including fatal torsade de pointes (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.
    Pasireotide: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of pasireotide with osimertinib is necessary; 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; 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 substrate that has been reported to prolong the QT interval. Osimertinib is a BCRP inhibitor.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of systemic pentamidine with osimertinib is necessary; 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. Systemic pentamidine has also been associated with QT prolongation.
    Perphenazine: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of perphenazine with osimertinib is necessary; 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. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of amitriptyline with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of perphenazine with osimertinib is necessary; 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. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) Avoid coadministration of 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of promethazine with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of short-acting beta-agonists such as albuterol and levalbuterol with osimertinib is necessary; 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. Beta-agonists may also 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of posaconazole with osimertinib is necessary; 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. Posaconazole has also been associated with prolongation of the QT interval as well as rare cases of torsade de pointes (TdP).
    Primaquine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of primaquine with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of procainamide with osimertinib is necessary; 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. Procainamide is also associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of prochlorperazine with osimertinib is necessary; 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. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of promethazine with osimertinib is necessary; 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. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Propafenone: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of propafenone with osimertinib is necessary; 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Protriptyline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of protriptyline with osimertinib is necessary; 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. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    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) Monitor electrolytes and ECGs for QT prolongation if coadministration of quinidine with osimertinib is necessary; 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. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
    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, 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. Quinine has also been associated with QT prolongation and rare cases of TdP.
    Ranolazine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ranolazine with osimertinib is necessary; 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. Ranolazine is also associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Regadenoson: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of regadenoson with osimertinib is necessary; 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. Regadenoson has also been associated with QT prolongation.
    Ribociclib: (Major) Avoid coadministration of ribociclib 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. 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). 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 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%.
    Rilpivirine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of rilpivirine with osimertinib is necessary; 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Risperidone: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of risperidone with osimertinib is necessary; 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. Risperidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP), primarily in the overdose setting.
    Ritonavir: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ritonavir with osimertinib is necessary; 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; the use of ritonavir could also result in QT prolongation.
    Romidepsin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of romidepsin with osimertinib is necessary; 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; romidepsin has also been reported to prolong the QT interval.
    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 may increase rosuvastatin plasma concentrations.
    Salmeterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of salmeterol with osimertinib is necessary; 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. Beta-agonists may also 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 electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Saquinavir 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.
    Selexipag: (Moderate) Use caution if coadministration of osimertinib with selexipag is necessary, due to the risk of increased selexipag exposure. Osimertinib is a BCRP inhibitor in vitro, and selexipag is a BCRP substrate. Coadministration of osimertinib with rosuvastatin, a BCRP substrate, increased the rosuvastatin AUC and Cmax by 35% and 72%, respectively; exposure to selexipag may also be expected to increase.
    Sertraline: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of sertraline with osimertinib is necessary; 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. There have also been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Sevoflurane: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of halogenated anesthetics with osimertinib is necessary; 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; halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of short-acting beta-agonists such as albuterol and levalbuterol with osimertinib is necessary; 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. Beta-agonists may also 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.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Solifenacin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of solifenacin with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Both drugs have been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use of solifenacin, although causality was not determined.
    Sorafenib: (Major) Closely monitor electrolytes and ECGs for QT prolongation if coadministration of sorafenib with osimertinib is necessary; 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 sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of sotalol with osimertinib is necessary; 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. Sotalol administration is also associated with QT prolongation as well as torsade de pointes (TdP); proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of St. Johns 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. Johns 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. Johns 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%.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of sulfamethoxazole with osimertinib is necessary; 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. QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) has also been reported during postmarketing use of sulfamethoxazole; trimethoprim. (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of trimethoprim with osimertinib is necessary; 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. QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) has also been reported during postmarketing use of sulfamethoxazole; trimethoprim.
    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) Monitor electrolytes and ECGs for QT prolongation if coadministration of sunitinib with osimertinib is necessary; 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. Sunitinib can also prolong the QT interval.
    Tacrolimus: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tacrolimus with osimertinib is necessary; 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 tacrolimus also causes QT prolongation.
    Tamoxifen: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tamoxifen with osimertinib is necessary; 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. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses; rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of telavancin with osimertinib is necessary; 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. Telavancin has also been associated with QT prolongation.
    Telithromycin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of telithromycin with osimertinib is necessary; 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. Telithromycin is also associated with QT prolongation, as well as torsade de pointes (TdP).
    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 substrate and osimertinib is a BCRP 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 substrate and osimertinib is a BCRP inhibitor.
    Terbutaline: (Minor) Monitor electrolytes and ECGs for QT prolongation if coadministration of short-acting beta-agonists such as albuterol and levalbuterol with osimertinib is necessary; 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. Beta-agonists may also 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.
    Tiotropium; Olodaterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of olodaterol with osimertinib is necessary; 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. Beta-agonists may also 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.
    Tizanidine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tizanidine with osimertinib is necessary; 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. Tizanidine administration may also result in QT prolongation.
    Tolterodine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tolterodine with osimertinib is necessary; 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. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Topotecan: (Major) Avoid coadministration of osimertinib with oral topotecan due to the potential for increased topotecan exposure; osimertinib may have less of an effect on intravenous topotecan and these may be administered with caution. Topotecan is a BCRP substrate and osimertinib is a BCRP inhibitor.
    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
    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) Monitor electrolytes and ECGs for QT prolongation if coadministration of trifluoperazine with osimertinib is necessary; 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. Trifluoperazine is also associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimethoprim: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of trimethoprim with osimertinib is necessary; 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. QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) has also been reported during postmarketing use of sulfamethoxazole; trimethoprim.
    Trimipramine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of trimipramine with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of triptorelin with osimertinib is necessary; 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. Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Umeclidinium; Vilanterol: (Moderate) Monitor electrolytes and ECGs for QT prolongation if coadministration of vilanterol with osimertinib is necessary; 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. 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) Monitor electrolytes and ECGs for QT prolongation if coadministration of vardenafil with osimertinib is necessary; 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. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Closely monitor electrolytes and ECGs for QT prolongation if coadministration of vemurafenib with osimertinib is necessary; 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 vemurafenib has been associated with QT prolongation.
    Venlafaxine: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of venlafaxine with osimertinib is necessary; 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. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Voriconazole: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of voriconazole with osimertinib is necessary; 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. Voriconazole has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Vorinostat: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of vorinostat with osimertinib is necessary; 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. Vorinostat 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.

    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.

    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 986 liters; plasma protein binding was 95%. The mean estimated half-life of osimertinib is 48 hours, and clearance (CL/F) is 14.2 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-gp, BCRP
    The main metabolic pathways of osimertinib are oxidation, predominately via CYP3A, and dealkylation in vitro. Osimertinib is also a P-glycoprotein (P-gp) and BCRP substrate 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. Additionally, osimertinib is a competitive inhibitor of CYP3A, but does not inhibit CYP2C8, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 2E1 in vitro. Osimertinib induced CYP3A4 (Pregnane X dependent) and CYP1A2.

    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 1000 calories and 58 grams of fat) was comparable to under fasting conditions.