Osimertinib (Monograph)

Brand name: Tagrisso
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide methanesulfonate
Molecular formula: C₂₈H₃₃N₇O₂•CH₄O₃S
CAS number: 1421373-66-1

Medically reviewed by Drugs.com on Jul 21, 2022. Written by ASHP.

Introduction

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

Uses for Osimertinib

Non-small Cell Lung Cancer (NSCLC)

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

First-line treatment of metastatic NSCLC harboring EGFR exon 19 deletions (del19) or exon 21 (L858R) substitution 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 patients who have experienced disease progression during or after EGFR tyrosine kinase inhibitor therapy.

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

Osimertinib Dosage and Administration

General

Pretreatment Screening

• Adjuvant therapy of NSCLC: Confirm presence of epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations in tumor specimens using an FDA-approved companion diagnostic test (e.g., cobas EGFR Mutation Test).

• First-line treatment of metastatic NSCLC: Confirm presence of EGFR del19 or L858R substitution mutations in tumor or plasma specimens using an FDA-approved diagnostic test (e.g., cobas EGFR Mutation Test). Patients with a negative plasma del19 or L858R mutation result should be reevaluated for feasibility of a tumor biopsy.

• Previously treated metastatic NSCLC: Confirm presence of EGFR T790M mutation in tumor or plasma specimens by an FDA-approved diagnostic test (e.g., cobas EGFR Mutation Test). Because of the high rate of false-negative results, plasma testing is recommended only when a tumor biopsy cannot be obtained; patients with a negative plasma result should be reevaluated for feasibility of a tumor biopsy.

• Baseline left ventricular ejection fraction (LVEF) in patients with cardiac risk factors.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor for symptoms of interstitial lung disease 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.

• Patients with cardiac risk factors: Monitor for signs and symptoms of cardiomyopathy during therapy; assess LVEF in patients with cardiac risk factors at baseline and in those who develop signs or symptoms of cardiomyopathy during therapy.

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).

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 NSCLC

Oral

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

First-line Treatment of Metastatic NSCLC

Oral

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

Previously Treated Metastatic NSCLC

Oral

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

Dosage Modification

Interstitial Lung Disease/Pneumonitis

Oral

If interstitial lung disease or pneumonitis occurs, permanently discontinue drug.

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 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.

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

If used concomitantly with a potent CYP3A inducer, increase osimertinib dosage to 160 mg daily.

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

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Interstitial Lung Disease/Pneumonitis

Severe or fatal interstitial lung disease or pneumonitis may occur.

Temporarily interrupt therapy and promptly evaluate patient if any respiratory manifestations suggestive of interstitial lung disease occur; permanently discontinue if a diagnosis is confirmed.

Prolongation of QT Interval

QT_c-interval prolongation reported. Appears to occur in a concentration-dependent manner.

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.

Assess cardiac function (including LVEF) in patients with cardiac risk factors prior to initiating therapy and periodically thereafter. Assess LVEF in any patient who develops cardiac complications during therapy.

Permanently discontinue in patients who develop symptomatic CHF.

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 and Stevens-Johnson Syndrome

Erythema multiforme and Stevens-Johnson syndrome reported in postmarketing case reports.

Withhold osimertinib if erythema multiforme 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.

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.

Impairment of Fertility

Based on animal studies, may impair female and male fertility.

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.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy based on age; however, a higher incidence of grade 3 or 4 adverse reactions and more frequent dosage modifications for adverse reactions observed in patients ≥65 years of age relative to younger adults.

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 reported in >20% of patients: Diarrhea, rash, musculoskeletal pain, dry skin, nail toxicity, stomatitis, fatigue, cough. Laboratory abnormalities reported in ≥20% of patients: Leukopenia, lymphopenia, anemia, thrombocytopenia, neutropenia.

Interactions for Osimertinib

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

Potent CYP3A 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 potent CYP3A 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. (See Prolongation of QT Interval under Cautions.)

Drugs Affecting Gastric Acidity

Clinically important pharmacokinetic interactions unlikely.

Specific Drugs

Osimertinib 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

• Importance of reading the manufacturer's patient information.

• Risk of severe or fatal interstitial lung disease/pneumonitis. 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. Importance of immediately informing clinician if any possible symptoms of QT-interval prolongation (e.g., dizziness, lightheadedness, syncope) occur.

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

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

• Risk of erythema multiforme and Stevens-Johnson syndrome. Importance of promptly informing clinician if target lesions or severe blistering/peeling of the skin occur.

• Risk of cutaneous vasculitis. 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 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. Importance of women informing their clinician if they are pregnant or think they may be pregnant. If pregnancy occurs, advise patient of potential fetal risk.

• Importance of advising women to avoid breast-feeding while receiving osimertinib therapy and for 2 weeks after the drug is discontinued.

• 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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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