Osimertinib Mesylate (Monograph)

Brand name: Tagrisso
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jan 10, 2025. Written by ASHP.

Introduction

Antineoplastic agent; a third-generation inhibitor of receptor tyrosine kinases.

Uses for Osimertinib Mesylate

Non-small Cell Lung Cancer (NSCLC)

Adjuvant treatment after tumor resection in adults with NSCLC harboring epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) mutations (as detected by an FDA-approved diagnostic test).

Treatment of adults with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations (as detected by an FDA-approved diagnostic test).

First-line treatment of adults with metastatic NSCLC harboring EGFR exon 19 deletions (del19) or exon 21 (L858R) mutations (as detected by an FDA-approved diagnostic test).

Treatment of metastatic NSCLC harboring EGFR T790M mutation (as detected by an FDA-approved diagnostic test) in adults who have experienced disease progression during or after EGFR tyrosine kinase inhibitor therapy.

First-line treatment, in combination with pemetrexed and platinum-based chemotherapy, of adults with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations (as detected by an FDA-approved diagnostic test).

Designated an orphan drug by FDA for treatment of EGFR mutation-positive NSCLC.

Guidelines from the American Society of Clinical Oncology (ASCO) strongly recommend osimertinib as a first-line treatment option for patients withEGFR exon 19 deletions or exon 21 L858R substitution mutations.

Osimertinib Mesylate Dosage and Administration

General

Pretreatment Screening

• Adjuvant therapy of NSCLC: Confirm presence of EGFR exon 19 deletions (del19) or exon 21 (L858R) mutations in tumor specimens using an FDA-approved companion diagnostic test.

• Locally advanced, unresectable (stage III) NSCLC: Confirm presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor specimens using an FDA-approved companion diagnostic test.

• First-line treatment of metastatic NSCLC as monotherapy: Confirm presence of EGFR exon 19 deletions or exon 21 L858R mutations in plasma or tumor specimens using an FDA-approved companion diagnostic test.

• First-line treatment of locally advanced or metastatic NSCLC in combination with pemetrexed and platinum-based chemotherapy: Confirm presence of EGFR exon 19 deletions or exon 21 L858R mutations in plasma or tumor specimens using an FDA-approved companion diagnostic test.

• Previously treated metastatic NSCLC: Confirm presence of EGFR T790M mutation in plasma or tumor specimens by an FDA-approved diagnostic test.

• Conduct cardiac monitoring, including an evaluation of left ventricular ejection fraction (LVEF), before initiating osimertinib as monotherapy in patients with cardiac risk factors and in all patients initiating osimertinib in combination with pemetrexed and platinum-based chemotherapy.

• Perform a CBC with differential before initiating osimertinib as monotherapy or in combination with pemetrexed and platinum-based chemotherapy.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor for symptoms of interstitial lung disease (ILD) and pneumonitis during therapy.

• Monitor for corrected QT (QT_c) interval prolongation in patients with congenital long QT_c syndrome, congestive heart failure, or electrolyte abnormalities, and those receiving concomitant drugs known to prolong the QT_c interval.

• Periodic monitoring of electrolyte concentrations recommended in patients with congenital long QT_c syndrome, congestive heart failure, or electrolyte abnormalities, and those receiving concomitant drugs known to prolong the QT_c interval.

• Conduct cardiac monitoring, including an LVEF assessment, during treatment in patients with cardiac risk factors receiving osimertinib as monotherapy and in all patients receiving osimertinib in combination with pemetrexed and platinum-based chemotherapy. Assess LVEF in patients who develop relevant cardiac signs or symptoms during therapy.

• Perform a CBC with differential periodically during therapy, and more frequently if clinically indicated.

Administration

Oral Administration

Administer orally once daily without regard to meals; swallow tablets whole and do not crush.

For patients with difficulty swallowing solids, may disperse tablet in a container with 60 mL (2 ounces) of noncarbonated water (do not use other liquids); immediately swallow. To ensure full dose is administered, rinse container with an additional 120–240 mL of water and drink immediately. Do not crush, heat, or ultrasonicate tablet when preparing drug dispersion.

Alternatively, for administration through a nasogastric tube, disperse tablet in a container with 15 mL of noncarbonated water and draw dispersion into a syringe; rinse container with additional 15 mL of water to transfer any residue to the syringe. Administer the resulting 30-mL drug dispersion through the nasogastric tube, then flush tube with appropriate volumes of water (approximately 30 mL). Repeat this step until no tablet pieces remain in the syringe. Administer the dispersion and residues within 30 minutes of the addition of the tablet to the water.

If a dose is missed, take next dose at regularly scheduled time; do not take missed dose.

Dosage

Available as osimertinib mesylate; dosage expressed in terms of osimertinib.

Adults

NSCLC

Adjuvant Treatment of EGFR Mutation-positive NSCLC

Oral

80 mg once daily. Continue therapy for up to 3 years or until disease recurrence or unacceptable toxicity occurs.

Locally Advanced, Unresectable (Stage III) EGFR Mutation-positive NSCLC

Oral

80 mg once daily following platinum-based chemoradiation therapy. Continue therapy until disease progression or unacceptable toxicity occurs.

First-line Therapy for EGFR Mutation-positive Metastatic NSCLC

Oral

80 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

First-line Therapy for EGFR Mutation-positive Locally Advanced or Metastatic NSCLC

Oral

80 mg once daily in combination with pemetrexed and platinum-based chemotherapy. Continue therapy until disease progression or unacceptable toxicity occurs.

Refer to the pemetrexed and cisplatin or carboplatin prescribing information for dosing information for these agents.

Previously Treated EGFR T790M Mutation-positive Metastatic NSCLC

Oral

80 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modifications

Pulmonary Effects

Oral

If any grade of interstitial lung disease (ILD) or pneumonitis occurs in patients who have not received recent definitive platinum-based chemoradiation therapy, permanently discontinue drug.

If grade 1 ILD/pneumonitis occurs in patients who have received recent definitive platinum-based chemoradiation therapy, withhold or continue osimertinib, as clinically indicated. If grade ≥2 ILD/pneumonitis occurs in these patients, permanently discontinue osimertinib.

Cardiac Effects

Oral

If QT_c interval >500 msec on at least 2 separate ECGs, withhold therapy. If QT_c interval improves to <481 msec or returns to baseline (if baseline QT_c interval ≥481 msec), may resume therapy at reduced dosage of 40 mg daily.

If QT_c-interval prolongation occurs concurrently with signs and/or symptoms of life-threatening arrhythmia, permanently discontinue drug.

If symptomatic congestive heart failure occurs, permanently discontinue drug.

Cutaneous Toxicity

Oral

If Stevens-Johnson syndrome, toxic epidermal necrolysis, or erythema multiforme major is suspected, withhold osimertinib. Permanently discontinue osimertinib if diagnosis confirmed.

If cutaneous vasculitis is suspected, withhold osimertinib and evaluate patient for systemic involvement; consider consultation with a dermatologist. Consider permanent discontinuance based on severity when no other etiology is identified.

Blood and Bone Marrow Toxicity

Oral

If aplastic anemia is suspected, withhold osimertinib. If confirmed, permanently discontinue therapy.

Other Toxicity

Oral

If other grade 3 or higher adverse effects occur, withhold therapy for up to 3 weeks.

If adverse effect improves to grade 0–2, resume therapy at original dosage or reduced dosage (40 mg daily); if no improvement within 3 weeks, permanently discontinue drug.

Concomitant Use with CYP3A Inducers

Oral

Avoid concomitant use of osimertinib with strong CYP3A4 inducers. If concomitant use with a strong CYP3A4 inducer is unavoidable, increase osimertinib dosage to 160 mg daily. Resume the usual dosage of 80 mg daily three weeks after the strong CYP3A4 inducer is discontinued.

Combination Therapy with Pemetrexed and Platinum-based Chemotherapy

When osimertinib is concomitantly administered with pemetrexed and platinum-based chemotherapy, modify the dose of any one of the treatments for the management of adverse reactions, as appropriate. For dosage modifications for osimertinib specifically, refer to the information above under Dosage Modifications. Withhold, reduce, or permanently discontinue the dosage of pemetrexed, cisplatin, or carboplatin according to their respective prescribing information.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B; total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN; or total bilirubin concentration 1–3 times ULN with any AST concentration): No dosage adjustment needed.

Severe hepatic impairment: Insufficient data to provide dosage recommendations.

Renal Impairment

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): No dosage adjustment needed.

End-stage renal disease: Insufficient data to provide dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Osimertinib Mesylate

Contraindications

• None.

Warnings/Precautions

Interstitial Lung Disease/Pneumonitis

Severe or fatal interstitial lung disease (ILD) or pneumonitis may occur.

For patients administered osimertinib who have not received recent definitive platinum-based chemoradiation therapy, withhold osimertinib therapy and promptly investigate for ILD in patients who present with worsening or respiratory symptoms suggestive of ILD (e.g., dyspnea, couth, fever). If a diagnosis of ILD is confirmed, permanently discontinue the drug.

For patients administered recent definitive platinum-based chemoradiation therapy with grade 1 ILD/pneumonitis, continue or interrupt osimertinib therapy and restart, as appropriate. Permanently discontinue the drug in patients with grade ≥2 ILD/pneumonitis.

Prolongation of QT Interval

QT_c-interval prolongation reported.

Periodically monitor ECG and serum electrolytes in patients with congenital long QT syndrome, congestive heart failure, or electrolyte abnormalities and in those receiving concomitant drugs known to prolong the QT interval with known risk of torsades de pointes.

If QT-interval prolongation occurs, dosage reduction, temporary interruption, or permanent discontinuance of therapy may be necessary.

Permanently discontinue if QT_c-interval prolongation is accompanied by signs and/or symptoms of life-threatening arrhythmia.

Cardiomyopathy

Cardiomyopathy (e.g., acute or chronic cardiac failure, CHF, pulmonary edema, decreased ejection fraction) reported.

In patients administered osimertinib monotherapy, assess cardiac monitoring (including LVEF) prior to initiating osimertinib and periodically during therapy in patients with cardiac risk factors.

In patients administered osimertinib in combination with pemetrexed and platinum-based chemotherapy, assess cardiac monitoring (including LVEF) prior to initiating osimertinib and periodically during therapy in all patients.

Assess LVEF in any patient who develops relevant cardiac signs or symptoms during osimertinib therapy. Permanently discontinue therapy in patients who develop symptomatic congestive heart failure.

Keratitis

Keratitis reported. If manifestations suggestive of keratitis (e.g., eye inflammation, lacrimation, photosensitivity, blurred vision, eye pain, red eye) occur, promptly refer patient to an ophthalmologist for evaluation.

Erythema Multiforme, Toxic Epidermal Necrolysis, and Stevens-Johnson Syndrome

Erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome reported in postmarketing case reports.

Withhold osimertinib if erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome suspected; permanently discontinue if diagnosis confirmed.

Cutaneous Vasculitis

Cutaneous vasculitis (e.g., leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis) reported in postmarketing case reports.

Withhold osimertinib if cutaneous vasculitis suspected and evaluate for systemic involvement; consider consultation with a dermatologist. Consider permanently discontinuing osimertinib based on severity when no other etiology is identified.

Aplastic Anemia

Aplastic anemia reported; some cases resulted in fatal outcomes. Advise patients of signs and symptoms of aplastic anemia (e.g., new or persistent fevers, bruising, bleeding, pallor). If suspected, withhold osimertinib and obtain a hematology consultation. If diagnosis is confirmed, permanently discontinue osimertinib. Perform CBC with differential before initiating therapy, periodically throughout treatment, and more frequently if indicated.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity (e.g., postimplantation loss and early embryonic death, decreased fetal weight) demonstrated in animals.

Verify pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Females of reproductive potential should use effective methods of contraception during therapy and for 6 weeks after drug discontinuance.

Males with female partners of reproductive potential should use effective methods of contraception during therapy and for 4 months after drug discontinuance.

Specific Populations

Pregnancy

No available data in pregnant women; animal studies and the drug's mechanism of action suggest possible fetal harm. If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.

Lactation

Not known whether distributed into human milk or if drug has any effect on milk production or nursing infant. Discontinue nursing during therapy and for 2 weeks after drug is discontinued.

Females and Males of Reproductive Potential

Verify pregnancy status prior to initiation of osimertinib therapy in females of reproductive potential and advise such females to use effective contraception during osimertinib therapy and for 6 weeks after the drug is discontinued. In addition, males with female partners of reproductive potential should use effective methods of contraception while receiving the drug and for 4 months after the drug is discontinued.

Results of animal studies suggest that osimertinib may impair female and male fertility.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In clinical trials of osimertinib monotherapy involving 1813 patients, 770 patients were ≥65 years of age and 207 patients were ≥75 years of age. Although no overall differences in efficacy or safety were observed between patients ≥65 years of age and younger patients, exploratory analysis suggested an increased incidence of ≥grade 3 adverse reactions (43% versus 33%) and more frequent dosage modifications for adverse reactions (34% versus 23%) in patients ≥65 years of age.

In a clinical study of osimertinib following definitive platinum-based chemoradiation therapy involving 142 patients, 62 patients were ≥65 years of age and 13 patients were ≥75 years of age. No overall differences in efficacy or safety were observed between patients ≥65 years of age and younger patients.

In a clinical study of osimertinib in combination with pemetrexed and platinum-based chemotherapy involving 276 patients, 104 patients were ≥65 years of age and 23 patients were ≥75 years of age. Clinical studies of combination therapy did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients; however, exploratory analysis suggested an increased incidence of ≥grade 3 adverse reactions (68% versus 61%) and more frequent dosage modifications for adverse reactions (55% versus 43%) in patients ≥65 years of age.

Hepatic Impairment

Pharmacokinetics of osimertinib not altered by mild to moderate hepatic impairment (Child-Pugh class A or B; total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN; or total bilirubin concentration 1–3 times ULN with any AST concentration).

Not studied in patients with severe (total bilirubin concentration 3–10 times ULN with any AST concentration) hepatic impairment.

Renal Impairment

Pharmacokinetics of osimertinib not altered by mild to severe renal impairment (Cl_cr 15–89 mL/minute).

Not studied in patients with end-stage renal disease (Cl_cr <15 mL/minute).

Common Adverse Effects

Adverse effects (>20%) receiving osimertinib as monotherapy: leukopenia, lymphophenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, fatigue.

Adverse effects (>20%) receiving osimertinib following platinum-based chemoradiation therapy: lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, COVID-19.

Adverse effects (>20%) receiving osimertinib in combination with pemetrexed and platinum-based chemotherapy: leukopenia, thrombocytopenia, neutropenia, lymphophenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, increased creatinine.

Drug Interactions

Metabolized principally by CYP3A. Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Induces CYP1A2. Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.

Inhibits BCRP, but does not inhibit organic anion transporter (OAT) 1 and OAT3, organic anion transporter polypeptide (OATP) 1B1 and OATP1B3, multidrug and toxin extrusion transporter (MATE) 1 and MATE2K, or organic cation transporter (OCT) 2.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 inducers: Possible pharmacokinetic interaction (decreased plasma osimertinib concentrations). Avoid concomitant use. If concomitant use cannot be avoided, increase osimertinib dosage to 160 mg daily; resume dosage of 80 mg daily 3 weeks after the strong CYP3A4 inducer is discontinued.

Drugs Transported by Breast Cancer Resistance Protein

Possible pharmacokinetic interaction (increased plasma concentrations of substrate). Monitor for adverse effects of BCRP substrate.

Drugs Affected by the P-gp Transport System

Possible pharmacokinetic interaction (increased plasma concentrations of substrate). Monitor for adverse effects of P-gp substrate.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation). Avoid concomitant use. If concomitant use cannot be avoided, periodically monitor ECG and electrolytes.

Drugs Affecting Gastric Acidity

Clinically important pharmacokinetic interactions unlikely.

Specific Drugs

Osimertinib Mesylate Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained approximately 6 hours (range 3–24 hours) after oral administration.

Dose-proportional increases in AUC and peak plasma concentration observed over a dose range of 20–240 mg.

Steady-state concentrations are achieved in approximately 15 days.

Food

Administration with a high-fat meal slightly increased AUC and peak plasma concentration by 19 and 14%, respectively; not considered clinically important.

Distribution

Extent

Not known whether distributed into milk. Limited animal data suggest that drug distributes into brain.

Plasma Protein Binding

95%.

Elimination

Metabolism

Principally metabolized by CYP3A.

Metabolized to 2 active metabolites (AZ7550 and AZ5104), each accounting for approximately 10% of total drug exposure.

AZ7550 has a similar potency to parent drug; AZ5104 exhibits higher potency against mutant EGFR and wild-type EGFR.

Elimination Route

Eliminated in feces (68%) and urine (14%); 2% eliminated as unchanged drug.

Half-life

Approximately 48 hours.

Special Populations

Age, weight, gender, smoking status, baseline albumin concentration, line of therapy, and race (Asian versus non-Asian) do not substantially affect pharmacokinetics of osimertinib.

Stability

Storage

Oral

Tablets

25°C (excursions permitted between 15–30°C).

Actions

• Binds irreversibly and selectively to mutant forms of EGFR including the EGFR-sensitizing mutations (e.g., exon 19 deletion [del19], exon 21 substitution [L858R]) and the secondary T790M mutation.

• Also inhibits HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, ACK1, and BLK in vitro.

• Demonstrates antitumor activity against NSCLC cell lines expressing EGFR L858R/T790M, L858R, T790M/del19, and del19 and, to a lesser extent, wild-type EGFR.

• Exhibits approximately ninefold greater affinity for mutant forms of EGFR than wild-type EGFR.

Advice to Patients

• Risk of severe or fatal interstitial lung disease/pneumonitis. Stress importance of immediately informing clinician if new or worsening respiratory symptoms (e.g., difficulty breathing, shortness of breath, cough, fever) occur.

• Risk of QT_c-interval prolongation. Stress importance of immediately informing clinician if any possible symptoms of QT-interval prolongation (e.g., dizziness, lightheadedness, syncope) occur.

• Risk of cardiomyopathy. Stress importance of immediately informing clinician if manifestations of heart failure (e.g., palpitations, shortness of breath, edema) occur.

• Risk of keratitis. Inform clinician if manifestations of keratitis (e.g., eye inflammation, lacrimation, photosensitivity, eye pain, red eye, changes in vision) occur.

• Risk of erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Promptly inform clinician if target lesions or severe blistering/peeling of the skin occur.

• Risk of cutaneous vasculitis. Stress importance of informing clinician if they develop multiple, non-blanching red papules on their extremities or buttocks, or large hives on their trunk that do not resolved within 24 hours and develop a bruised appearance.

• Risk of aplastic anemia. Inform clinician if signs and symptoms develop such as new or persistent fevers, bruising, bleeding, or pallor.

• Risk of fetal harm. Advise females of reproductive potential to use effective methods of contraception during therapy and for 6 weeks after drug discontinuance. Advise males with female partners of reproductive potential to use effective methods of contraception during therapy and for 4 months after drug is discontinued. Stress importance of women informing their clinician if they are pregnant or think they may be pregnant. If pregnancy occurs, advise the patient of potential fetal risk.

• Advise females to avoid breast-feeding while receiving osimertinib therapy and for 2 weeks after the drug is discontinued.

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Osimertinib mesylate can only be obtained through a limited network of specialty distributors. Consult manufacturer's website for additional information.

Reload page with references included

Frequently asked questions

• What is Tagrisso used for?

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